Compounds as tyrosine kinase modulators

ABSTRACT

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/444,161, filed Jul. 28, 2014, which is a continuation in part of U.S.application Ser. No. 12/875,223, filed Sep. 3, 2010, now U.S. Pat. No.8,809,534, issued Aug. 19, 2014, which claims priority under 35 U.S.C.119(e) to U.S. Provisional Application No. 61/239,603, filed on Sep. 3,2009, 61/306,616, filed on Feb. 22, 2010, 61/356,699 filed on Jun. 21,2010 and 61/360,531 filed on Jul. 1, 2010, all of which are expresslyincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to novel compounds with multiplearomatic components capable of modulating, regulating and/or inhibitingtyrosine kinase signal transduction. The present invention is alsodirected to methods of prevention and/or treatment of disorders relatedto unregulated tyrosine kinase signal transduction, including but notlimited to, cell growth disorders, metabolic disorders, blood vesselproliferative disorders, inflammatory disorders, neurodegenerativediseases and immune disorders.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (“PTKs”) play an important role in the controlof cell growth and differentiation. PTKs comprise a large and diverseclass of proteins having enzymatic activity. PTKs can be of thereceptor-type (having extracellular, transmembrane and intracellulardomains) or the non-receptor type (being wholly intracellular). Forexample, signal transduction mediated by receptor tyrosine kinases(“RTKs”) is initiated by extracellular interaction with a specificgrowth factor (i.e., a ligand), followed by receptor dimerization,transient stimulation of the intrinsic protein tyrosine kinase activityand phosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolichomeostasis, and responses to the extracellular microenvironment).

With respect to RTKs, it has been shown also that tyrosinephosphorylation sites function as high-affinity binding sites for SH2(src homology) domains of signaling molecules. Several intracellularsubstrate proteins that associate with RTKs have been identified and aredivided into two principal groups: (1) substrates which have a catalyticdomain; and (2) substrates which lack a catalytic domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors or proteins and SH2domains of their substrates is determined by the amino acid residuesimmediately surrounding the phosphorylated tyrosine residue. Differencesin binding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each RTK is determined not only by its pattern of expression andligand availability, but also by the array of downstream signaltransduction pathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

The RTKs comprise a large family of transmembrane receptors with diversebiological activities. The intrinsic function of RTKs is activated uponligand binding, which results in phophorylation of the receptor andmultiple cellular substrates, and subsequently in a variety of cellularresponses. At present, at least nineteen distinct RTK subfamilies havebeen identified. One RTK subfamily, designated the HER subfamily, isbelieved to be comprised of EGFR, HER2, HER3 and HER4. Ligands to theHER subfamily of receptors include epithelial growth factor (EGF),TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. The secondsubfamily of RTKs, designated the insulin subfamily, is comprised of theINS—R, the IGF-1R and the IR—R. The third RTK subfamily, the “PDGF”family, includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the kinase insert domain-receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (fit-1). Each of these receptors was initially believed to be areceptor for hematopoietic growth factors. Two other subfamilies of RTKshave been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 andFGFR4) and the Met subfamily (c-met and Ron). Because of thesimilarities between the PDGF and FLK subfamilies, the two subfamiliesare often considered together. The known RTK subfamilies are identifiedin Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated hereinby reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps,Fak, Jak, Ack and LIMK) have been identified. At present, the Srcsubfamily of non-receptor tyrosine kinases is comprised of the largestnumber of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr andYrk. The Src subfamily of enzymes has been linked to oncogenesis. A moredetailed discussion of non-receptor tyrosine kinases is provided inBolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein byreference.

Many of the protein tyrosine kinases (PTKs), whether an RTK ornon-receptor tyrosine kinase, have been found to be involved in cellularsignaling pathways leading to cellular signal cascades and pathogenicconditions such as cancer, psoriasis and hyper immune responses. In viewof the importance of PTKs to the control, regulation and modulation ofcell proliferation and the diseases and disorders associated withabnormal cell proliferation, many attempts have been made to identifyreceptor and non-receptor tyrosine kinase “inhibitors” using a varietyof approaches, including the use of mutant ligands (U.S. Pat. No.4,966,849), soluble receptors and antibodies (Kendall & Thomas, 1994,Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362:841-844), RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56);Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp.Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152:448-57) and tyrosine kinase inhibitors (U.S. Pat. No. 5,330,992;Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).

More recently, attempts have been made to identify small molecules whichact as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclicor heterocyclic aryl compounds (PCT Application No. WO 92/20642),vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have beendescribed generally as tyrosine kinase inhibitors. Styryl compounds(U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S.Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No.0 566 266 A1), seleoindoles and selenides (PCT Application No. WO94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO92/21660) and benzylphosphonic acid compounds (PCT Application No. WO91/15495) have been described as compounds for use as tyrosine kinaseinhibitors for use in the treatment of cancer.

In addition, other small molecules were studied as tyrosine kinaseinhibitors, such as the compounds disclosed in U.S. Pat. Nos. 6,765,012;6,541,504; 6,747,025; 5,792,783; 5,834,504; 5,883,113; 5,883,116 and5,886,020, all of which are incorporated by reference in theirentireties.

The identification and use of compounds which specifically inhibitsignal transduction by modulating the activity of receptor andnon-receptor tyrosine is one aspect of the present invention.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by Formula Icapable of modulating, regulating and/or inhibiting tyrosine kinasesignal transduction, and uses of the compounds and compositionsincorporating the compounds for disease treatment and prevention.

The compounds of the present invention can be found in general FormulaI:

wherein

-   -   X is selected from the group consisting of NR¹, O, S(O)_(n);    -   n is 0 or an integer of from 1 to 2;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(N R²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(I) is selected from the group consisting of hydrogen,        halogen, C₁ to C₈ alkyl, S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        O(CR⁵R⁶)_(d)Ar, S(O)_(f)(CR⁵R⁶)_(d)Ar, (CR⁵R⁶)_(d)S(O)_(f)R⁴,        NR⁴(CR⁵R⁶)_(d)S(O)_(f)R⁴, O(CR⁵R⁶)_(d) S(O)_(f)R⁴,        S(O)_(f)(CRR⁶)_(e)S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)N(R⁴)₂,        NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂, O(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)OR⁴, (CR⁵R⁶)_(d)OSO₂R⁴,        S(O)_(f)(CR⁵R⁶)_(e)OSO₂R⁴, (CR⁵R⁶)_(d)P(O)(OR⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)P(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, C(O)N═S(O)R⁵R⁶, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂,        (CR⁵R⁶)_(d)R⁵, S(O)_(f)(CR⁵R⁶)_(d)R⁵, HNC(O)R⁴, HN—C(O)OR⁴,        (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f) (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate;    -   a is 0 or an integer of from 1 to 3;    -   d is 0 or an integer of from 1 to 5;    -   e is an integer of from 1 to 4;    -   f is 0 or an integer of from 1 to 2;    -   R^(II) is independently selected from the group consisting of        hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy,        aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,        hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl,        (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl,        wherein R² and R³ are independently selected from the group        consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,        arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;        alternatively R² and R³ and may be taken together to form a 5-7        membered heterocyclic ring with N;    -   b is 0 or an integer of from 1 to 2;    -   Y is selected from the group consisting of        -   (1) —(CH₂)g-O—(CH₂)h-;        -   (2) —(CH₂)g-NR—(CH₂)h-;        -   (3) —(CH₂)g-CO—(CH₂)h-;        -   (4) —(CH₂)g-C(O)NR²—(CH₂)h-;        -   (5) —(CH₂)g-NR²C(O)—(CH₂)h-;        -   (6) —(CH₂)g-(CH₂)h-;        -   (7) —(CH₂)g-CH(OH)—(CH₂)h-;        -   (8) —(CH₂)g-C═C—(CH₂)h-;    -    and (9) a single bond;    -   wherein    -   g is 0 or an integer of from 1 to 3;    -   h is 0 or an integer of from 1 to 3;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(N R²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,        haloalkylsulfonyl, and heterocyclylsulfonyl;        Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which has 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which has 1-6heteroatoms independently selected from the group consisting of O, N andS;R^(III) represents optionally 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;Z is selected from the group consisting of

-   -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁸)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j);

wherein

-   -   i is 0 or 1;    -   j is 0 or 1;    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl.        Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which has 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which has 1-3heteroatoms independently selected from the group consisting of O, N andS;R^(IV) represents optionally 1-3 substituents, independently selectedfrom the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR⁹R¹⁰; wherein R⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl.

Some embodiments of the present invention are included in the followingparagraphs:

-   -   1) A compound according to Formula I, including any tautomer,        stereoisomer, diastereoisomeric form, polymorphic form, crystal        form, a solvate, a hydrate, a metabolite, a pharmaceutically        acceptable salt or prodrug, mixture of different stereoisomers,        mixture of different crystal forms.    -   2) A compound of Formula I in the form of a prodrug.    -   3) The compound according to paragraph 1, wherein Y is selected        from the group consisting of        -   (a) —(CH₂)g-C═C—(CH₂)h-;        -   (b) —(CH₂)g-NR—(CH₂)h-;        -   (c) —(CH₂)g-CO—(CH₂)h-;        -   (d) —(CH₂)g-C(O)NR²—(CH₂)h-;        -   (e) —(CH₂)g-NR²C(O)—(CH₂)h-;        -   (f) —(CH₂)g-(CH₂)h-;        -   (g) —(CH₂)g-CH(OH)—(CH₂)h-;        -   (h) —(CH₂)g-O—(CH₂)h-;        -   and (i) a single bond.    -   4) The compound according to paragraphs 1-3, wherein Z is        selected from the group consisting of        (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j),        (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j), (CH₂)_(i)N(R⁷)C(O), and        C(O)N(R⁸)(CH₂)_(j).    -   5) The compound according to paragraphs 1-4, wherein X is NH.    -   6) The compound according to paragraphs 1-5, wherein Ring A and        Ring B are independently selected from the group consisting of

-   -   7) The compound according to paragraph 6, wherein X is S.    -   8) The compound according to paragraph 1, which can be further        represented by Formula II:

-   -   -   including any tautomer, stereoisomer, diastereoisomeric            form, crystal form, polymorphic form, mixture of            stereoisomers, mixture of polymorphic forms, mixture of            crystal forms, a solvate, a hydrate, a metabolite, a            pharmaceutically acceptable salt or a prodrug.

    -   9) The compound according to paragraphs 1-8, wherein R^(I) is        selected from the group consisting of hydrogen, halogen, C₁ to        C₈ alkyl, (CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        (CR⁵R⁶)_(d)C(O)N(R⁴)₂, NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        O(CR⁵R⁶)_(d)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂, (CR⁵R⁶)_(d)R⁵,        HNC(O)R⁴, HN—C(O)OR⁴, (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f)        (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate.

    -   10) A compound selected from the group consisting of

-   -   11) A method of use of the compounds of paragraphs 1-10, wherein        the compounds are    -   12) Use of the compounds of paragraphs 1-10 in the preparation        of a medicament for the treatment or prevention of diseases or        conditions related with unregulated tyrosine kinase activities,        comprising administering a therapeutically effective amount of        the compound of paragraphs 1-10 together with a pharmaceutically        acceptable carrier;    -   13) The use of paragraph 12, wherein the diseases or conditions        are selected from the group consisting of cell growth and        metabolic disorders, blood vessel proliferative disorders,        inflammatory disorders, neurodegenerative diseases, and immune        disorders.    -   14) The use of paragraphs 12-13 wherein the diseases or        conditions are selected from the group consisting of colorectal        cancer, lung cancer, hematological cancer, renal cancer, liver        cancer, breast cancer, diabetic retinopathy, macular        degeneration, age-related macular degeneration, retinopathy of        prematurity, ocular angiogenesis, retinal edema, retinal        ischemia, diabetic macular edema, cystoid macular edema, retinal        vein occlusion, branch vein occlusion, preretinal        neovascularization, laser-induced choroidal neovascularization,        neovascularization associated with keratoplasty, glaucoma and        ocular tumors, arthritis, restenosis, hepatic cirrhosis,        atherosclerosis, psoriasis, diabetes mellitus, wound healing,        inflammation, neurodegenerative diseases and immune disorders.    -   15) A pharmaceutical composition comprising a therapeutic        effective amount of a compound according to paragraphs 1-10        together with a pharmaceutically acceptable carrier which is        suitable for systematic, parenteral, local or topical delivery.    -   16) The pharmaceutical composition of paragraph 15 which are in        the form selected from the group consisting of tablets,        capsules, intravenous injections, intramuscular injections,        local injections, topical creams, gels and ointments, eye drops,        ophthalmic solutions, ophthalmic suspensions, ophthalmic        emulsions, intravitreal injections, subtenon injections,        ophthalmic biodrodible implant, and non-bioeordible ophthalmic        inserts or depots.    -   17) Use of the compounds of paragraph 10 in the preparation of a        medicament for the treatment of diseases and conditions, wherein        the medicament contains a pharmaceutical acceptable composition        according to paragraphs 15 and 16.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a series of compounds with multiplearomatic components useful as protein tyrosine kinase inhibitors. Thecompounds of the present invention are useful for treating diseasesrelated to unregulated tyrosine kinase signal transduction, for example,cancer, blood vessel proliferative disorders, fibrotic disorders, andneurodegenerative diseases. In particular, compounds of the presentinvention are useful for the treatment of colorectal cancer, lungcancer, hematological cancer, renal cancer, liver cancer, breast cancer,diabetic retinopathy, macular degeneration, age-related maculardegeneration, retinopathy of prematurity, ocular angiogenesis, retinaledema, retinal ischemia, diabetic macular edema, cystoid macular edema,retinal vein occlusion, branch vein occlusion, preretinalneovascularization, laser-induced choroidal neovascularization,neovascularization associated with keratoplasty, glaucoma and oculartumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, diabetes mellitus, wound healing, inflammation,neurodegenerative diseases and immune disorders.

1. Compounds of the Invention

The present invention is directed to a compound of Formula I:

-   -   wherein    -   X is selected from the group consisting of NR¹, O, S(O)₁;    -   n is 0 or an integer of from 1 to 2;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(N R²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(I) is selected from the group consisting of hydrogen,        halogen, C₁ to C₈ alkyl, S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        O(CR⁵R⁶)_(d)Ar, S(O)_(f)(CR⁵R⁶)_(d)Ar, (CR⁵R⁶)_(d)S(O)_(f)R⁴,        NR⁴(CR⁵R⁶)_(d)S(O)_(f)R⁴, O(CR⁵R⁶)_(d) S(O)_(f)R⁴,        S(O)_(f)(CR⁵R⁶)_(e)S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)N(R⁴)₂,        NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂, O(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)OR⁴, (CR⁵R⁶)_(d)OSO₂R⁴,        S(O)_(f)(CR⁵R⁶)_(e)OSO₂R⁴, (CR⁵R⁶)_(d)P(O)(OR⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)P(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, C(O)N═S(O)R⁵R⁶, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂,        (CR⁵R⁶)_(d)R⁵, S(O)_(f)(CR⁵R⁶)_(d)R⁵, HNC(O)R⁴, HN—C(O)OR⁴,        (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f) (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate;    -   a is 0 or an integer of from 1 to 3;    -   d is 0 or an integer of from 1 to 5;    -   e is an integer of from 1 to 4;    -   f is 0 or an integer of from 1 to 2;    -   R^(II) is independently selected from the group consisting of        hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy,        aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,        hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl,        (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl,        wherein R² and R³ are independently selected from the group        consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,        arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;        alternatively R² and R³ and may be taken together to form a 5-7        membered heterocyclic ring with N;    -   b is 0 or an integer of from 1 to 2;    -   Y is selected from the group consisting of        -   (1′) —(CH₂)g-O—(CH₂)h-;        -   (2′) —(CH₂)g-NR¹—(CH₂)h-;        -   (3′) —(CH₂)g-CO—(CH₂)h-;        -   (4′) —(CH₂)g-C(O)NR²—(CH₂)h-;        -   (5′) —(CH₂)g-NR²C(O)—(CH₂)h-;        -   (6′) —(CH₂)g-(CH₂)h-;        -   (7′) —(CH₂)g-CH(OH)—(CH₂)h-;        -   (8′) —(CH₂)g-C═C—(CH₂)h-;    -   and (9′) a single bond;    -   wherein    -   g is 0 or an integer of from 1 to 3;    -   h is 0 or an integer of from 1 to 3;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(N R²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,        haloalkylsulfonyl, and heterocyclylsulfonyl;        Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which has 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which has 1-6heteroatoms independently selected from the group consisting of O, N andS;R^(III) represents optionally 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;Z is selected from the group consisting of

-   -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁷)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j).

wherein

-   -   i is 0 or 1;    -   j is 0 or 1;    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl;

Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which has 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which has 1-3heteroatoms independently selected from the group consisting of O, N andS;R^(IV) represents optionally 1-3 substituents, independently selectedfrom the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR⁹R¹⁰; wherein R⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl.

Unless otherwise indicated, reference to a compound should be construedbroadly to include compounds, pharmaceutically acceptable salts,prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solidforms, crystal forms, polymorphic forms, hydrates, solvates,metabolites, mixtures of stereoisomers, mixtures of crystal forms,non-covalent complexes, and combinations thereof, of a chemical entityof a depicted structure or a chemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A “prodrug” is a compound, which when administered to the body of asubject (such as a mammal), breaks down in the subject's metabolicpathway to provide an active compound of Formula I. More specifically, aprodrug is an active or inactive “masked” compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject or patient. One common formof a prodrug is a masked carboxylic acid group. Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bundgaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use. For example, conversion may occurby hydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion. Unless stereochemistry is explicitly andunambiguously depicted, a structure is intended to include everypossible stereoisomer, both pure or in any possible mixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be amorphous forms, crystal forms, polymorphs,and the mixtures thereof.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

2. Uses, Formulation and Administration

The present invention is also directed to the use of the compounds asprotein tyrosine kinase modulators and inhibitors. These compounds canbe used to treat diseases related to unregulated tyrosine kinase signaltransduction, for example, various cancers, blood vessel proliferativedisorders, fibrotic disorders, and neurodegenerative diseases. Inparticular, compounds of the present invention are useful for thetreatment and/or prevention of colorectal cancer, lung cancer,hematological cancer, renal cancer, liver cancer, breast cancer,diabetic retinopathy, macular degeneration, age-related maculardegeneration, retinopathy of prematurity, ocular angiogenesis, retinaledema, retinal ischemia, diabetic macular edema, cystoid macular edema,retinal vein occlusion, branch vein occlusion, preretinalneovascularization, laser-induced choroidal neovascularization,neovascularization associated with keratoplasty, glaucoma and oculartumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, diabetes mellitus, wound healing, inflammation,neurodegenerative diseases and immune disorders in the human being.

The present invention is also directed to the preparation of amedicament for the treatment and prevention of diseases and conditionsrelated with abnormal activities of tyrosine kinase receptors. Themedicament contains a pharmaceutical acceptable composition, whichcomprises the therapeutic effective amount of the compounds of presentinvention, together with a pharmaceutical acceptable carrier.

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the diagnosis, cure, mitigation, treatment, or prevention ofdisease or other undesirable conditions.

The pharmaceutical acceptable compositions contain therapeutic effectiveamount of the compounds of the present invention. These compositions canbe used as a medicament and administered to a mammal, such as a person,in need thereof. Different types of suitable dosage forms andmedicaments are well known in the art, and can be readily adapted fordelivery of the compounds of the present invention, such as, but notlimited to, systematic, parenteral, local and topical delivery. Thedosage forms can be tablets, capsules, intravenous injections,intramuscular injections, local injections, topical creams, gels andointments, eye drops, ophthalmic solutions, ophthalmic suspensions,ophthalmic emulsions, intravitreal injections, subtenon injections,ophthalmic biodrodible implant, and non-bioeordible ophthalmic insertsor depots, nasal sprays and ointment, various rectal or vaginalpreparations.

3. Examples

TABLE 1 Exemplified Compounds of the Present Invention CompoundStructure MW Chemical Name F1

451 methyl 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate F2

437 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid F3

451 methyl 7-[3-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate F4

435 methyl 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate F5

421 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid F6

509 3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoic acid F7

527 3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid F8

455 7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid F9

469 methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2- b]pyridine-2-carboxylate F10

541 methyl 3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate F11

523 methyl 3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoateAdditional compounds of the present invention are listed below.

Example# Chemical Structure MW Chemical Name 12

547 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide 13

533 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2- b]pyridine-2-carboxamide 14

649 ethyl (4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin- 1-yl)acetate 15

592 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin- 1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide 16

594 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin- 4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide 17

622 methyl rel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4- hydroxypyrrolidine-2-carboxylate 18

556 methyl ({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino) acetate 19

566 dimethyl 2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino) diacetate 20

638 N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide 21

494 tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate 21A

594 N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide 22

493 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine- 2-carboxamide 23

639 ethyl 4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1- carboxylate 24

653 ethyl 4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine- 1-carboxylate 25

584 methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate 26

656 dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}imino)diacetate 27

642 dimethyl 2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate 28

567 methyl 1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate 29

736 ethyl (4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin- 1-yl)acetate 30

610 ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate 31

570 methyl ({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate 32

498 N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide 33

598 tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate 34

595 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide 35

571 N-(2,2-diethoxyethyl)-7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] thieno[3,2-b]pyridine-2-carboxamide 36

610 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- {3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2- carboxamide 37

612 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3- [2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2- carboxamide 38

596 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide 39

640 methyl (2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate 40

585 N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide 41

496 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- (2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide 42

624 methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine- 2-carboxylate 43

566 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- (3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide 44

612 tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate 45

512 N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide 46

612 (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5- oxopentanoic acid 47

668 tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl) amino]-5-oxopentanoate 48

641 (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5- oxopentanoic acid 49

655 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl) amino]pentanedioate 50

610 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine- 3-carboxylic acid 51

666 tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine- 3-carboxylate 52

511 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- (3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide 53

513 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- (3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide 54

613 dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate 55

582 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N- (3-morpholin-4-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide 56

551 ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate 57

569 ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate 58

531 N-[dimethyl(oxido)-λ-4-sulfanylidene]-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridine-2-carboxamide 59

603 4-[N-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoic acid 60

585 4-[N-({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoic acid 61

513 N-[dimethyl(oxido)-lambda~4~- sulfanylidene]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide 62

512 [({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]acetic acid 63

495 [({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]acetic acid 64

541 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid 65

523 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid 66

561 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide 67

577 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1- yl)propyl]thieno[3,2-b]pyridine-2-carboxamide 68

547 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide 69

535 N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide 70

549 N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide 71

408 Methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine- 2-carboxylate 72

394 7-{3-[(3-methyl-2-furoyl) amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid 73

421 N-ethyl-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide 74

449 N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine- 2-carboxamide 75

409 N-hydroxy-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide 76

451 N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide 77

437 N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide 78

489 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2- b]pyridine-2-carboxamide 79

452 3-hydroxypropyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate 80

438 2-hydroxyethyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate 81

452 2-methoxyethyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate 82

522 Methyl [(3-{[(7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl) amino]acetate 83

436 Methyl 7-(3-((2-fluoro-5-methylphenyl) carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate 84

422 7-(3-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid 85

449 N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2- b]pyridine-2-carboxamide 86

477 N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2- b]pyridine-2-carboxamide 87

550 Methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino) propyl]amino}acetate

3.1 Compound Synthesis and Characterization Compound F1 Methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate

To a stirred solution of methyl7-bromothieno[3,2-b]pyridine-2-carboxylate (200 mg, 0.74 mmol) in 8 mlof DMSO, were added CuBr (10 mg, 0.074 mmol), ethyl2-cyclohexanonecarboxylate (26 mg, 0.15 mmol), cesium carbonate (500 mg,1.54 mmol) and 4-aminophenol (96 mg, 0.88 mmol). The mixture was purgedwith nitrogen for 10 minutes, and then heated at 70° C. under N₂ for 3hours. The reaction was cooled to room temperature and poured into 100ml of water. The precipitates were filtered, washed with water and driedto give the crude aniline intermediate as a pale green solid (˜140 mg).This crude material was dissolved in 10 ml of THF, and2-fluoro-5-methylphenyl isocyanate (70 mg, 0.46 mmol) was added. Themixture was stirred at room temperature for 5 hours, and poured into 100ml of water. The brown precipitates were filtered, washed with water anddried to give the crude product, which was purified by silica gelchromatography, eluting with 2-3% MeOH/CHCl₃ to give methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylateas light brown solid. Yield: 90 mg, 27%.

¹H NMR (d₆-DMSO) d: 9.25 (s, 1H), 8.61 (d, J=5.3 Hz, 1H), 8.50 (br. s.,1H), 8.21 (s, 1H), 7.96 (d, J=6.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.25(d, J=8.8 Hz, 2H), 7.09 (dd, J=11.4, 8.2 Hz, 1H), 6.71-6.85 (m, 2H),3.91 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 452 (MH), 474 (M+Na⁺)

LR MS (ES−): 450 (M−H)

Compound F27-[4-({[(2-Fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid

To a stirred suspension of methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate(50 mg, 0.11 mmol) in MeOH (3 ml), was added 0.4M LiOH/MeOH solution (10ml, 4.0 mmol). The mixture was heated at 50° C. for 7 hours, and pouredinto 100 ml of water. 1M HCl was added until pH=4. The resultingprecipitates were filtered, washed with water and dried in vacuo to give7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid as light grey solid. Yield: 40 mg, 83%.

¹H NMR (DMSO-d₆) δ: 13.88 (br. s., 1H), 9.19 (s, 1H), 8.58 (d, J=5.3 Hz,1H), 8.47 (d, J=2.6 Hz, 1H), 8.10 (s, 1H), 7.96 (dd, J=7.9, 1.8 Hz, 1H),7.53-7.59 (m, 2H), 7.22-7.27 (m, 2H), 7.08 (dd, 1H), 6.77-6.80 (m, 1H),6.73 (d, J=5.6 Hz, 1H), 2.25 (s, 3H)

LR MS (ES−): 436 (M−H)

Compound F3 Methyl7-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate

prepared using procedures similar to Compound F1.

¹H NMR (DMSO-d₆) δ: 9.51 (s, 1H), 8.64 (d, J=5.3 Hz, 1H), 8.60 (s, 1H),8.21 (s, 1H), 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.58 (t, J=2.1 Hz, 1H), 7.41(t, J=8.1 Hz, 1H), 7.23 (dd, J=8.2, 1.2 Hz, 1H), 7.06 (dd, J=11.3, 8.4Hz, 1H), 6.91 (dd, J=7.9, 1.8 Hz, 1H), 6.85 (d, J=5.3 Hz, 1H), 6.77 (td,J=5.2, 2.2 Hz, 1H), 3.91 (s, 3H), 2.21 (s, 3H)

LR MS (ES+): 452 (MH), 474 (M+Na⁺)

LR MS (ES−): 450 (M−H)

Compound F4 Methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate

To a mixture of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (68mg, 0.25 mmol) and1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea(102 mg, 0.28 mmol) in 8 ml of 1,4-dioxane, was added PdCl₂(PPh₃)₂ (10mg, 0.014 mmol) and 1M Na₂CO₃ aqueous solution (0.25 ml, 0.5 mmol). Themixture was heated at 70° C. under N₂ for 1 hour, cooled to roomtemperature and poured into 100 ml of water. The brown precipitates werefiltered, washed with water and dried to give the crude product, whichwas purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl₃to give methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylateas light yellow solid. Yield: 30 mg, 28%.

¹H NMR (d₆-DMSO) d: 9.38 (s, 1H), 8.84 (d, J=4.7 Hz, 1H), 8.58 (d, J=2.1Hz, 1H), 8.28 (s, 1H), 7.60-8.06 (m, 6H), 7.06-7.19 (m, 1H), 6.82 (br.s., 1H), 3.93 (s, 3H), 2.28 (s, 3H)

LR MS (ES−): 434 (M−H)

Compound F57-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylicacid

To a stirred solution of methyl7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate(20 mg, 0.046 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH (2.0 ml,2.0 mmol). The mixture was heated at 70° C. for 30 minutes, cooled toroom temperature and poured into 50 ml of water. 1M HCl was added untilpH=4 and the resulting precipitates were filtered, washed with water anddried in vacuo to give7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylicacid.

Yield: 20 mg, 100%.

LR MS (ES−): 420 (M−H)

Preparation of 7-chlorothieno[3,2-b]pyridine

Thieno[3,2-b]pyridin-7-ol (20 g, 0.132 mol) was suspended in phosphorousoxy chloride (80.9 g, 0.528 mol) and stirred at 100 □C for 2 hours. Thesolution was cooled to room temperature and was poured over ice. Theaqueous solution was neutralized with sodium hydroxide and the resultingprecipitate was collected by filtration and washed with water. Thefilter cake was taken up in dichloromethane and dried over magnesiumsulfate. The solution was filtered and the filtrate was concentrated todryness to give 7-chlorothieno[3,2-b]pyridine as a brown liquid whichsolidified to a beige solid under high vacuum. Yield: 20.4 g (91%); MS[M+H]⁺ 169.9; ¹HNMR (CDCl₃) δ: □8.7 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H),7.3 (d, 1H) ppm.

Preparation of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate

7-chlorothieno[3,2-b]pyridine (19.7 g, 0.116 mol) was taken up in THF(400 mL) and cooled to approximately −70 □C. The n-butyllithium (1.6M,80 mL, 0.128 mol) was added dropwise with stirring under an atmosphereof nitrogen. The solution was stirred at −70 □C for 1 hour at which timeneat methyl chloroformate was added via dropwise addition. The reactionmixture gradually warmed to room temperature and was stirred for overthe weekend. The reaction mixture was treated with 25 mL of methanol andthen concentrated to dryness leaving a maroon residue. The crude solidwas taken up in dichloromethane and passed through a silica gel columneluting with 1:1 hexane/ethyl acetate. Fractions containing the productwere combined and concentrated to give a red solid. Trituration with 9:1hexane/diethyl ether afforded methyl7-chlorothieno[3,2-b]pyridine-2-carboxylate as a pink solid afterfiltration. Yield: 14.5 g (55%); MS [M+H]⁺ 227.9; ¹HNMR (CDCl₃) δ: □8.7(d, 1H), 8.3 (s, 1H), 7.4 (d, 1H) ppm.

Preparation of methyl7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate

Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (5 g, 0.022 mol) andthe 4-amino-3-fluorophenol (3.3 g, 0.026 mol) were added to a roundbottom flask containing cesium carbonate (14.8 g, 0.045 mol),ethyl-2-cyclohexanone carboxylate (0.73 g, 0.004 mol), and copper (I)chloride (0.22 g, 0.002 mol). The mixture was diluted with DMSO (250 mL)and stirred at 70 □C under an atmosphere of nitrogen for 2 hours. Thedark reaction mixture was cooled to room temperature and poured intoethyl acetate (500 mL)/water (1 L) with vigorous stirring. The mixturewas filtered through celite and the organic portion of the filtrate wasseparated and dried over magnesium sulfate. The solution was filteredand the filtrate was concentrated to give a purple viscous liquid. Thecrude product was taken up in dichloromethane and passed through asilica gel column eluting with 1:1 hexane/ethyl acetate. Fractionscontaining the product were combined and concentrated to afford methyl7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate as redsolid. Yield: 1.62 g (23%); MS [M+H]⁺ 319.1

Compound F9 methyl7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate

Methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate(1.62 g, 5.1 mmol) was taken up in 55 mL of ethyl acetate followed bythe dropwise addition of 2-fluoro-5-methylphenyl isocyanate (0.85 g, 5.6mmol) in 5 mL ethyl acetate. The solution afforded a lavender solidafter stirring at room temperature for overnight. The solid wascollected by filtration and washed with diethyl ether to give methyl7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylateas an off white solid.

Yield: 1.75 g (73%); MS [M+H]⁺ 470.1; ¹HNMR (DMSO-d₆) δ: □9.2 (s, 1H),9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H, 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d,1H), 7.2 (m, 2H), 6.8 (m, 2H), 3.9 (s, 3H), 2.1 (s, 3H) ppm.

Compound F10 methyl3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate

¹H NMR (DMSO-d₆) δ: 9.10 (br. s., 1H), 9.03 (t, J=5.4 Hz, 1H), 8.96 (br.s., 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.21 (s, 1H),7.98 (d, J=7.6 Hz, 1H), 7.40 (dd, J=11.6, 2.5 Hz, 1H), 7.06-7.16 (m,2H), 6.74-6.84 (m, 2H), 3.60 (s, 3H), 3.48-3.55 (m, 2H), 2.62 (t, J=6.9Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 563 (M+Na⁺)

LR MS (ES−): 539 (M−H)

Compound F11 methyl3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate

A mixture of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl)}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.27 mmol), HATU (122 mg, 0.32 mmol) andN,N-diisopropylethylamine (105 mg, 0.81 mmol) in anhydrous THF (10 ml)was stirred at room temperature for 10 minutes, followed by addition of(R)-3-pyrrolidinol (56 mg, 0.40 mmol). The mixture was heated andstirred at 60° C. for 30 minutes and poured into 100 ml of water. 2M HClwas added dropwise until pH=4. The precipitates were filtered, washedwith water and dried in vacuo to give methyl3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoateas white solid. Yield: 128 mg, 90%.

¹H NMR (DMSO-d₆) δ: 9.18 (s, 1H), 9.01 (t, 1H), 8.54 (br. s., 1H), 8.47(br. s., 1H), 8.20 (br. s., 1H), 7.95 (d, J=6.7 Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.08 (dd, J=11.0, 8.7 Hz, 1H), 6.78(br. s., 1H), 6.69 (d, J=5.0 Hz, 1H), 3.60 (s, 3H), 3.46-3.55 (m, 2H),2.62 (t, J=6.7 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 545 (M+Na⁺)

LR MS (ES−): 521 (M−H)

Compound F63-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoicacid

To a stirred solution of methyl3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate(98 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) wasadded 2 ml of 1M NaOH (2 mmol) solution. The mixture was stirred at roomtemperature for 1 hour and poured into 100 ml of water. 2M HCl was addeduntil pH=4. The resulting precipitates were filtered, washed with water,and dried in vacuo to give3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoicacid as off-white solid. Yield: 90 mg, 95%.

¹H NMR (DMSO-d₆) δ: 12.25 (br. s., 1H), 9.18 (s, 1H), 8.99 (t, J=5.1 Hz,1H), 8.54 (d, J=5.6 Hz, 1H), 8.47 (br. s., 1H), 8.21 (s, 1H), 7.95 (d,J=6.5 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.08 (dd,J=11.0, 8.4 Hz, 1H), 6.78 (br. s., 1H), 6.68 (d, J=5.3 Hz, 1H),3.42-3.53 (m, 2H), 2.53 (t, J=6.9 Hz, 2H), 2.25 (s, 3H)

LR MS (ES−): 507 (M−H)

Compound F73-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoicacid

¹H NMR (DMSO-d₆) δ: 12.26 (br. s., 1H), 9.09 (br. s., 1H), 9.00 (t,J=4.7 Hz, 1H), 8.96 (br. s., 1H), 8.56 (d, J=5.3 Hz, 1H), 8.25 (t, J=9.0Hz, 1H), 8.22 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.35-7.44 (m, 1H),7.05-7.16 (m, 2H), 6.71-6.85 (m, 2H), 3.42-3.54 (m, 2H), 2.53 (t, J=6.7Hz, 2H), 2.25 (s, 3H)

LR MS (ES−): 525 (M−H)

Compound F87-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid

Methyl7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate(1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwiseaddition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution wasstirred at room temperature for 3 hours, at which time an additional 2.4mL of 1N sodium hydroxide was added. The solution was stirred at roomtemperature for overnight and the resulting mixture was diluted with 75mL of water and acidified using 1N HCl. The insoluble material wasseparated by filtration and the filter cake was suspended in ethylacetate and stirred for several minutes before filtering. The filtercake was washed several times with ethyl acetate and dried under highvacuum to give7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid as an off white solid. Yield: 1.6 g (90%); MS [M+H]⁺ 456.1; ¹HNMR(DMSO-d₆) δ: □13.9 (bs, 1H), □9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3(t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m,2H), 2.1 (s, 3H) ppm.

Other compounds which may be made according to the teachings of thepresent application include:

Synthesis and Characterization of the additional compounds is listedbelow.

Example 12

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (Compound F1) (100 mg, 0.23 mmol) in 10 ml of anhydrousacetonitrile were added HATU (95 mg, 0.25 mmol) andN,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred atroom temperature for 20 minutes, followed by addition of3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (57 mg, 0.35 mmol). Themixture was stirred at room temperature for another 40 minutes andpoured into 100 ml of water with vigorous stirring. 1M HCl was addeddropwise until pH=5. The precipitates were filtered, washed with waterand dried in vacuo to give the crude, which was purified by silica gelchromatography eluting with 8˜12% methanol in chloroform containing 0.5%of triethylamine to give7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamideas white solid. Yield: 50 mg, 40%.

¹H NMR (DMSO-d₆): 9.28 (s, 1H), 9.18 (t, J=5.6 Hz, 1H), 8.57 (d, J=5.6Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.26 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.80-6.82 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 3.37-3.40 (m, 2H),2.87-2.91 (m, 2H), 2.27 (s, 3H), 1.98 (quin, J=7.3 Hz, 2H)

LR MS (ES−): 545 (M−H)

The following Example 13 was prepared using the experiment proceduredescribed in Example 12, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 13

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (DMSO-d₆): 9.22 (s, 1H), 9.12 (t, J=5.9 Hz, 1H), 8.57 (d, J=5.6Hz, 1H), 8.51 (d, J=2.9 Hz, 1H), 8.18 (s, 1H), 7.98 (dd, J=8.4, 1.9 Hz,1H), 7.57-7.60 (m, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.24-7.27 (m, 1H), 7.25(d, J=9.1 Hz, 1H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H),6.72 (d, J=5.6 Hz, 1H), 3.66-3.69 (m, 2H), 3.20 (t, J=7.0 Hz, 2H), 2.28(s, 3H)

LR MS (ES−): 531 (M−H)

Example 14

ethyl(4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate

To a stirred solution of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide(180 mg, 0.36 mmol) and 1-(ethoxycarbonylmethyl)piperazine (124 mg, 0.72mmol) in anhydrous DMF was added 2 drops of acetic acid. The solutionwas stirred at room temperature for 30 minutes, followed by addition of1M NaCNBH₃ solution in THF (0.72 ml, 0.72 mmol). Stirring was continuedfor another hour, and the mixture was poured into 100 ml of water. Theprecipitates were filtered to give the crude, which was purified bysilica gel chromatography eluting with 8-12% of methanol in chloroformto give ethyl(4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetateas light yellow solid. Yield: 70 mg, 30%.

¹H NMR (DMSO-d₆): 9.20 (s, 1H), 8.90 (t, J=5.7 Hz, 1H), 8.53 (d, J=5.3Hz, 1H), 8.48 (dd, J=2.3, 0.6 Hz, 1H), 8.19 (s, 1H), 7.93-7.98 (m, 1H),7.53-7.58 (m, 2H), 7.20-7.24 (m, 2H), 7.08 (dd, J=11.4, 8.5 Hz, 1H),6.75-6.81 (m, 1H), 6.68 (d, J=5.6 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H),3.25-3.33 (m, 2H), 3.15 (s, 2H), 2.27-2.43 (m, 10H), 2.25 (s, 3H), 1.68(quin, J=7.1 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H)

LR MS (ES+): 671 (M+Na⁺)

LR MS (ES−): 647 (M−H)

The following Examples 15 through 17 were prepared using the experimentprocedure described in Example 14, but with the appropriate reagent,reaction conditions and reactant substitutions that will be readilyrealized by those of ordinary skill in this art without the exercise ofundue experimentation.

Example 15

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide

LR MS (ES+): 592 (MH⁺)

Example 16

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide

LR MS (ES+): 616 (M+Na⁺)

LR MS (ES−): 592 (M−H)

Example 17

methylrel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate

¹H NMR (DMSO-d₆): 9.22 (s, 1H), 8.92 (t, J=5.6 Hz, 1H), 8.56 (d, J=5.6Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.6, 2.1 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 4.89 (d, J=4.4 Hz, 1H),4.20-4.26 (m, 1H), 3.61 (s, 3H), 3.40 (t, J=7.8 Hz, 1H), 3.32-3.36 (m,2H), 3.25-3.28 (m, 1H), 2.70 (dt, J=12.0, 7.5 Hz, 1H), 2.49-2.52 (m,1H), 2.28 (s, 3H), 2.26-2.29 (m, 1H), 1.96-2.01 (m, 1H), 1.89 (td,J=8.4, 4.0 Hz, 1H), 1.63-1.71 (m, 2H)

LR MS (ES+): 622 (MH⁺)

LR MS (ES−): 620 (M−H)

The following Example 18 was prepared using the experiment proceduredescribed in Example 25, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 18

methyl({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate

¹H NMR (DMSO-d₆): 9.22 (s, 1H), 8.95 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.8, 2.2 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.80-6.83 (m, 1H), 6.72 (s, 1H), 3.63 (s, 3H), 3.38 (s, 2H),3.32-3.36 (m, 2H), 2.61 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.69 (quin,J=7.0 Hz, 2H)

LR MS (ES−): 564 (M−H)

The following Example 19 was prepared using the experiment proceduredescribed in Example 26, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 19

dimethyl2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate

¹H NMR (DMSO-d₆): 9.21 (s, 1H), 8.88 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.3Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.21 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 3.60 (s, 6H), 3.54 (s,4H), 3.32-3.35 (m, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.67(quin, J=6.9 Hz, 2H)

LR MS (ES+): 660 (M+Na⁺)

LR MS (ES−): 636 (M−H)

Example 20

N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of tert-butyl{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate(380 mg, 0.64 mmol) in 10 ml of methylene chloride was added 5 ml oftrifluoroacetic acid. The mixture was stirred at room temperature for 30minutes and evaporated to dryness under reduced pressure. The residuewas re-dissolved in MeOH (5 ml) and poured into 100 ml of water withvigorous stirring. Saturated NaHCO₃ solution was added until pH=8˜9. Theprecipitates were filtered, washed with water and dried in vacuo to giveN-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideas yellow solid. Yield: 270 mg, 85%.

LR MS (ES+): 516 (M+Na⁺)

LR MS (ES−): 492 (M−H)

Example 21

tert-butyl{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate

A mixture of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (300 mg, 0.69 mmol), HATU (288 mg, 0.76 mmol) andN,N-diisopropylethylamine (196 mg, 1.52 mmol) in anhydrous acetonitrile(10 ml) was stirred at room temperature for 30 minutes, followed byaddition of N-Boc-1,3-propanediamine (180 mg, 1.03 mmol). The mixturewas stirred for another 30 minutes and poured into 100 ml of water withvigorous stirring. 2M HCl was added dropwise until pH=6. Theprecipitates were filtered, washed with water and dried in vacuo to givetert-butyl{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamateas brown solid. Yield: 380 mg, 93%.

¹H NMR (DMSO-d₆): 9.25 (s, 1H), 8.89 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.3Hz, 1H), 8.53 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.6, 2.1 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.26 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.81 (ddd, J=10.9, 5.4, 2.8 Hz, 1H), 6.71 (d, J=5.6 Hz, 1H),6.70-6.72 (m, 1H), 3.27-3.30 (m, 2H), 3.00 (q, J=6.7 Hz, 2H), 2.28 (s,3H), 1.67 (quin, J=7.1 Hz, 2H), 1.38 (s, 9H)

LR MS (ES+): 616 (M+Na⁺)

LR MS (ES−): 592 (M−H)

Example 21A Preparation ofN-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (600 mg, 1.37 mmol) in 10 ml of anhydrous acetonitrile were addedHATU (608 mg, 1.6 mmol) and N,N-diisopropylethylamine (388 mg, 3.0mmol). The mixture was stirred at room temperature for 30 minutes,followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol).The mixture was stirred for another 10 minutes and poured into 100 ml ofwater with vigorous stirring. 1M HCl was added until pH=5. Theprecipitates were filtered, washed with water and dried in vacuo to giveN-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideas yellow solid. Yield: 680 mg, 88%.

¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 8.90 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.6Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.9, 2.1 Hz,1H), 7.57-7.60 (m, 2H), 7.24-7.28 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz,1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.3 Hz, 1H), 4.59 (t, J=5.6 Hz, 1H),3.60 (dq, J=9.4, 7.0 Hz, 2H), 3.46 (dq, J=9.4, 7.0 Hz, 2H), 3.32-3.36(m, 2H), 2.28 (s, 3H), 1.81-1.85 (m, 2H), 1.12 (t, J=7.0 Hz, 6H)

LR MS (ES+): 589 (M+Na⁺)

LR MS (ES−): 565 (M−H)

Example 22

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide

To a stirred solution ofN-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide(680 mg, 1.20 mmol) in 10 ml of THF was added 1 ml of 2M HCl. Themixture was stirred at room temperature for 3 hours, and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was addeduntil pH=9. The precipitates were filtered, washed with water and driedin vacuo to give7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamideas brown solid. Yield: 550 mg, 93%.

LR MS (ES+): 515 (M+Na⁺)

LR MS (ES−): 491 (M−H)

Example 23

ethyl4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1-carboxylate

¹H NMR (DMSO-d₆) δ: 9.13 (d, J=2.6 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.92(t, J=5.9 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.29 (t, J=9.1 Hz, 1H), 8.24(s, 1H), 8.01 (dd, J=7.8, 2.2 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H),7.12-7.16 (m, 1H), 7.12 (dd, J=11.4, 8.5 Hz, 1H), 6.80-6.85 (m, 1H),6.80 (d, J=5.6 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H), 3.43 (q, J=6.5 Hz, 2H),3.36 (t, J=5.0 Hz, 4H), 2.51-2.56 (m, 2H), 2.39-2.44 (m, 4H), 2.28 (s,3H), 1.17 (t, J=7.0 Hz, 3H)

LR MS (ES+): 639 (MH+)

LR MS (ES−): 637 (M−H)

The following Example 24 was prepared using the experiment proceduredescribed in Example 38, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 24

ethyl4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate

¹H NMR (DMSO-d₆) δ: 9.13 (d, J=2.6 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.94(t, J=5.6 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.29 (t, J=9.2 Hz, 1H), 8.24(s, 1H), 8.01 (dd, J=7.9, 2.3 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H),7.09-7.16 (m, 2H), 6.79-6.85 (m, 1H), 6.80 (d, J=5.3 Hz, 1H), 4.02 (q,J=7.0 Hz, 2H), 3.32-3.38 (m, 6H), 2.31-2.40 (m, 6H), 2.28 (s, 3H), 1.73(quin, J=6.9 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H)

LR MS (ES+): 653 (MH⁺)

LR MS (ES−): 651 (M−H)

Example 25

methyl({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate

To a stirred solution ofN-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide(125 mg, 0.24 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in10 ml of anhydrous DMF was added methyl bromoacetate (36 mg, 0.24 mmol).The mixture was stirred at room temperature for 50 minutes and pouredinto 100 ml of water with vigorous stirring. The precipitates werefiltered and dried in vacuo to give the crude, which was purified bysilica gel chromatography eluting with 5˜8% of MeOH in CHCl₃ to affordmethyl({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetateas light beige solid. Yield: 54 mg, 38%.

¹H NMR (DMSO-d₆): 9.10 (d, J=1.8 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.93(t, J=5.6 Hz, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20(s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H),7.11 (dd, J=9.0, 2.5 Hz, 1H), 7.09 (dd, J=11.4, 8.2 Hz, 1H), 6.78-6.81(m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.59 (s, 3H), 3.32 (s, 2H), 3.29-3.34(m, 2H), 2.56 (t, J=6.7 Hz, 2H), 2.25 (s, 3H), 1.65 (quin, J=7.0 Hz, 2H)

LR MS (ES+): 584 (MH⁺)

LR MS (ES−): 582 (M−H)

Example 26

dimethyl2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate

To a stirred solution ofN-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide(125 mg, 0.24 mmol) and N,N-diisopropylethylamine (77 mg, 0.60 mmol) in10 ml of anhydrous DMF was added methyl bromoacetate (92 mg, 0.60 mmol).The mixture was heated at 60° C. for 1 hour and poured into 100 ml ofwater with vigorous stirring. The precipitates were filtered and driedin vacuo to give the crude, which was purified by silica gelchromatography eluting with 3˜4% of MeOH in CHCl₃ to afford dimethyl2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetateas white solid. Yield: 140 mg, 88%.

¹H NMR (DMSO-d₆): 9.10 (d, J=2.1 Hz, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.86(t, J=5.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20(s, 1H), 7.98 (dd, J=7.8, 2.5 Hz, 1H), 7.39 (dd, J=11.6, 2.8 Hz, 1H),7.11 (dd, J=9.2, 2.8 Hz, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82(m, 1H), 6.77 (d, J=5.6 Hz, 1H), 3.58 (s, 6H), 3.51 (s, 4H), 3.29-3.33(m, 2H), 2.69 (t, J=6.9 Hz, 2H), 2.25 (s, 3H), 1.64 (quin, J=7.0 Hz, 2H)

LR MS (ES+): 677 (MNa+)

LR MS (ES−): 654 (M−H)

The following Example 27 was prepared using the experiment proceduredescribed in Example 26, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 27

dimethyl2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate

¹H NMR (acetone) d: 8.59 (d, J=5.3 Hz, 1H), 8.56 (br. s., 1H), 8.46 (t,J=9.1 Hz, 1H), 8.42 (d, J=2.9 Hz, 1H), 8.40 (t, J=5.0 Hz, 1H), 8.15-8.18(m, 1H), 8.15 (s, 1H), 7.25 (dd, J=11.6, 2.8 Hz, 1H), 7.13-7.17 (m, 1H),7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.86 (m, 1H), 6.78 (d, J=5.3 Hz,1H), 3.69 (s, 6H), 3.68 (s, 4H), 3.42-3.48 (m, 2H), 3.00 (t, J=5.9 Hz,2H), 2.32 (s, 3H)

LR MS (ES+): 642 (MH⁺)

LR MS (ES−): 640 (M−H)

The following Example 28 was prepared using the experiment proceduredescribed in Example 30, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 28

methyl1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate

LR MS (ES+): 567 (MH⁺)

LR MS (ES−): 565 (M−H)

Example 29

ethyl(4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin-1-yl)acetate

The title compound was isolated as a side product in the preparation ofethyl[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate.

LR MS (ES+): 736 (MH⁺)

LR MS (ES−): 734 (M−H)

Example 30

ethyl[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate

A mixture of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (100 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) andN,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydroustetrahydrofuran (10 ml) was heated at 60° C. for 10 minutes, followed byaddition of ethyl piperazinoacetate (57 mg, 0.33 mmol). Heating wascontinued at 60° C. for 30 minutes and the mixture was poured into 100ml of water. The precipitates were filtered, washed with water and driedin vacuo to give the crude, which was purified by silica gelchromatography eluting with 3˜5% methanol in chloroform to give ethyl[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetateas white solid. Yield: 73 mg, 54%.

¹H NMR (DMSO-d₆) δ: 9.11 (br. s., 1H), 8.97 (br. s., 1H), 8.56 (d, J=5.6Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.80 (s, 1H),7.39 (dd, J=11.7, 2.3 Hz, 1H), 7.06-7.13 (m, 2H), 6.78-6.81 (m, 1H),6.77 (d, J=5.3 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.66 (br. s., 4H), 3.27(s, 2H), 2.58 (br. s., 4H), 2.25 (s, 3H), 1.16 (t, J=7.2 Hz, 3H)

LR MS (ES+): 610 (MH⁺)

LR MS (ES−): 608 (M−H)

The following Example 31 was prepared using the experiment proceduredescribed in Example 25, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 31

methyl({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate

¹H NMR (DMSO-d₆): 9.10 (s, 1H), 8.96 (s, 1H), 8.89 (t, J=5.7 Hz, 1H),8.56 (d, J=5.6 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.22 (s, 1H), 7.98 (d,J=8.2 Hz, 1H), 7.39 (dd, J=11.7, 2.3 Hz, 1H), 7.10-7.13 (m, 1H), 7.09(dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz, 1H),3.59 (s, 3H), 3.36 (s, 2H), 3.31-3.35 (m, 2H), 2.70 (t, J=6.5 Hz, 2H),2.25 (s, 3H)

LR MS (ES+): 570 (MH⁺)

Example 32

N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of tert-butyl{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate(488 mg, 0.82 mmol) in 10 ml of dichloromethane was added 5 ml oftrifluoroacetic acid. The mixture was stirred at room temperature forone hour and evaporated to dryness under reduced pressure. The residuewas re-dissolved in MeOH (5 ml) and poured into 100 ml of water withvigorous stirring. Saturated NaHCO₃ solution was added until pH=8˜9. Theprecipitates were filtered, washed with water and dried in vacuo to giveN-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideas brown solid. Yield: 400 mg, 99%.

LR MS (ES+): 498 (MH⁺)

LR MS (ES−): 496 (M−H)

Example 33

tert-butyl{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate

A mixture of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (400 mg, 0.88 mmol), HATU (400 mg, 1.05 mmol) andN,N-diisopropylethylamine (250 mg, 1.94 mmol) in anhydrous THF (10 ml)was heated at 60° C. for 15 minutes, followed by addition ofN-Boc-ethylenediamine (210 mg, 1.32 mmol). The mixture was stirred at60° C. for another 5 minutes, cooled to room temperature and poured into100 ml of water with vigorous stirring. 2M HCl was added dropwise untilpH=5. The precipitates were filtered, washed with water and dried invacuo to give tert-butyl{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamateas off-white solid. Yield: 518 mg, 99%.

¹H NMR (DMSO-d₆) δ: 9.12 (d, J=1.8 Hz, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.95(t, J=5.9 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.28 (t, J=9.1 Hz, 1H), 8.22(s, 1H), 8.01 (dd, J=7.8, 2.2 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H),7.10-7.15 (m, 2H), 6.95 (t, J=6.0 Hz, 1H), 6.81-6.84 (m, 1H), 6.80 (d,J=5.6 Hz, 1H), 3.31-3.34 (m, 2H), 3.14 (q, J=6.6 Hz, 2H), 2.28 (s, 3H),1.37 (s, 9H)

LR MS (ES+): 598 (MH⁺)

LR MS (ES−): 596 (M−H)

Example 34

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide

A mixture of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (100 mg, 0.22 mmol), HATU (90 mg, 0.24 mmol) andN,N-diisopropylethylamine (55 mg, 0.43 mmol) in anhydrous acetonitrile(10 ml) was stirred at room temperature for 30 minutes, followed byaddition of 3-(4-methylpiperazin-1-yl)propan-1-amine (40 mg, 0.25 mmol).The mixture was stirred for another 10 minutes and poured into 100 ml ofwater. The precipitates were filtered, washed with water and dried invacuo to give7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamideas brown solid. Yield: 110 mg, 84%.

¹H NMR (acetone): 8.56-8.60 (m, 2H), 8.42-8.49 (m, 3H), 8.14-8.18 (m,1H), 8.06 (s, 1H), 7.24 (dd, J=11.6, 2.8 Hz, 1H), 7.14 (dt, J=8.9, 2.0Hz, 1H), 7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.86 (m, 1H), 6.78 (d,J=5.3 Hz, 1H), 3.49 (q, J=6.5 Hz, 2H), 2.48 (t, J=6.5 Hz, 2H), 2.39 (br.s., 8H), 2.32 (s, 3H), 2.18 (s, 3H), 1.80 (quin, J=6.6 Hz, 2H)

LR MS (ES+): 595 (MH⁺)

LR MS (ES−): 593 (M−H)

Example 35

N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

The following Examples 36 and 37 were prepared using the experimentprocedure described in Example 38, but with the appropriate reagent,reaction conditions and reactant substitutions that will be readilyrealized by those of ordinary skill in this art without the exercise ofundue experimentation.

Example 36

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide

LR MS (ES+): 610 (MH⁺)

LR MS (ES−): 608 (M−H)

Example 37

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide

LR MS (ES+): 612 (MH⁺)

LR MS (ES−): 610 (M−H)

Example 38

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl)propyl]thieno[3,2-b]pyridine-2-carboxamide

To a stirred solution of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide(150 mg, 0.29 mmol) in 10 ml of anhydrous DMF were added4-hydroxypiperidine (59 mg, 0.58 mmol) and acetic acid (10 mg, 0.17mmol). The mixture was stirred at room temperature for 40 minutes,followed by addition of 1M sodium cyanoborohydride solution in THF (0.60ml, 0.60 mmol) and stirring was continued for another 30 minutes. Themixture was poured into 100 ml of water. The precipitates were filtered,washed with water and dried to give the crude, which was purified bysilica gel flash chromatography eluting with 10-20% of MeOH in CHCl₃ togive7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamideas white solid. Yield: 70 mg, 40%.

¹H NMR (DMSO-d₆): 9.11 (s, 1H), 8.97 (s, 1H), 8.94 (br. s., 1H), 8.56(d, J=5.3 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.06-7.14 (m, 2H), 6.79 (td,J=5.3, 2.3 Hz, 1H), 6.77 (d, J=5.3 Hz, 1H), 4.56 (br. s., 1H), 3.44 (br.s., 1H), 3.36 (br. s., 2H), 2.76 (br. s., 2H), 2.28-2.45 (m, 2H), 2.25(s, 3H), 2.05 (br. s., 2H), 1.71 (br. s., 4H), 1.39 (br. s., 2H)

LR MS (ES+): 596 (MH⁺)

LR MS (ES−): 594 (M−H)

The following Example 39 was prepared using the experiment proceduredescribed in Example 42, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 39

methyl(2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate

¹H NMR (acetone): 8.66 (t, J=6.2 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.56(d, J=2.1 Hz, 1H), 8.45 (t, J=9.1 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H),8.14-8.17 (m, 1H), 8.08 (s, 1H), 7.24 (dd, J=11.6, 2.8 Hz, 1H), 7.14(dt, J=9.1, 1.6 Hz, 1H), 7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.85 (m,1H), 6.78 (d, J=5.3 Hz, 1H), 4.35-4.44 (m, 1H), 4.05 (d, J=4.1 Hz, 1H),3.72 (s, 3H), 3.59-3.67 (m, 1H), 3.56 (t, J=8.2 Hz, 1H), 3.39-3.52 (m,2H), 2.87-2.94 (m, 1H), 2.66 (dt, J=12.5, 4.7 Hz, 1H), 2.38 (dd, J=10.0,4.1 Hz, 1H), 2.32 (s, 3H), 2.07-2.14 (m, 2H), 1.74-1.83 (m, 1H),1.65-1.74 (m, 1H)

LR MS (ES+): 640 (MH⁺)

LR MS (ES−): 638 (M−H)

Example 40

N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (1.0 g, 2.2 mmol) in 20 ml of anhydrous tetrahydrofuran were addedHATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (620 mg, 4.8 mmol).The mixture was heated at 60° C. for 20 minutes, followed by addition of1-amino-3,3-diethoxypropane (388 mg, 2.6 mmol). The mixture was heatedat 60° C. for another 30 minutes, cooled to room temperature and pouredinto 100 ml of water with vigorous stirring. The precipitates werefiltered, washed with water and dried in vacuo to giveN-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideas off-white solid. Yield: 1.23 g, 95%.

¹H NMR (DMSO-d₆): 9.10 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.89(t, J=5.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20(s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H),7.10-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H),6.77 (d, J=5.6 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 3.57 (dq, J=9.4, 7.0 Hz,2H), 3.43 (dq, J=9.7, 7.0 Hz, 2H), 3.29-3.34 (m, 2H), 2.25 (s, 3H),1.75-1.85 (m, 2H), 1.09 (t, J=7.0 Hz, 6H)

LR MS (ES+): 607 (MNa+)

LR MS (ES−): 583 (M−H)

Example 41

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide

To a stirred solution ofN-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide(300 mg, 0.53 mmol) in 10 ml of THF was added 2 ml of 2M HCl. Themixture was heated under nitrogen at 60° C. for 4 hours, cooled to roomtemperature, and poured into 100 ml of water with vigorous stirring.Saturated NaHCO₃ solution was added until pH=7. The precipitates werefiltered, washed with water and dried in vacuo to give7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamideas white solid. Yield: 250 mg, 96%.

LR MS (ES+): 497 (MH⁺)

LR MS (ES−): 495 (M−H)

Example 42

methyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate

To a stirred solution of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide(150 mg, 0.29 mmol) in 10 ml of anhydrous DMF was added L-proline methylester hydrochloride (96 mg, 0.58 mmol) and triethylamine (58 mg, 0.58mmol). The mixture was stirred at room temperature under nitrogen forone hour, and 1M solution of sodium cyanoborohydride in THF (0.60 ml,0.60 mmol) was added. The mixture was stirred for another hour, andpoured into 100 ml of water. The precipitates were filtered, washed withwater and dried in vacuo to give the crude product, which was purifiedby silica gel chromatography eluting with 2˜3% of methanol in chloroformto afford methyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylateas white solid. Yield: 90 mg, 50%.

¹H NMR (DMSO-d₆): 9.10 (s, 1H), 8.96 (s, 1H), 8.92 (t, J=5.7 Hz, 1H),8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.18 (s, 1H), 7.95-8.01(m, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.06-7.13 (m, 2H), 6.78-6.82 (m,1H), 6.77 (d, J=5.9 Hz, 1H), 3.58 (s, 3H), 3.29-3.34 (m, 2H), 3.15-3.21(m, 1H), 2.97-3.05 (m, 1H), 2.67 (dt, J=11.9, 7.6 Hz, 1H), 2.40-2.45 (m,1H), 2.29-2.38 (m, 1H), 2.25 (s, 3H), 2.02 (dq, J=12.0, 8.2 Hz, 1H),1.76-1.81 (m, 1H), 1.70-1.76 (m, 2H), 1.60-1.70 (m, 2H)

LR MS (ES+): 624 (MH⁺)

LR MS (ES−): 622 (M−H)

The following Example 43 was prepared using the experiment proceduredescribed in Example 34, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 43

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl)}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (DMSO-d₆): 9.10 (dd, J=2.1, 0.6 Hz, 1H), 8.93-8.98 (m, 2H), 8.56(d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.19 (s, 1H), 7.98 (dd,J=7.9, 2.3 Hz, 1H), 7.39 (dd, J=11.6, 2.8 Hz, 1H), 7.10-7.13 (m, 1H),7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz,1H), 3.29-3.34 (m, 2H), 2.37-2.45 (m, 6H), 2.25 (s, 3H), 1.70 (quin,J=7.0 Hz, 2H), 1.63-1.67 (m, 4H)

LR MS (ES+): 566 (MH⁺)

LR MS (ES−): 564 (M−H)

Example 44

tert-butyl{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate

A mixture of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (300 mg, 0.66 mmol), HATU (277 mg, 0.73 mmol) andN,N-diisopropylethylamine (187 mg, 1.45 mmol) in anhydrous acetonitrile(10 ml) was stirred at room temperature for 30 minutes, followed byaddition of N-Boc-1,3-propanediamine (172 mg, 0.99 mmol). The mixturewas stirred for another 10 minutes and poured into 100 ml of water withvigorous stirring. 2M HCl was added dropwise until pH=5. Theprecipitates were filtered, washed with water and dried in vacuo to givetert-butyl{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamateas light yellow solid. Yield: 345 mg, 85%.

¹H NMR (DMSO-d₆): 9.10 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.87(t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.21(s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H),7.11 (ddd, J=9.0, 2.9, 1.0 Hz, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H),6.78-6.83 (m, 2H), 6.77 (d, J=5.3 Hz, 1H), 3.24-3.28 (m, 2H), 2.97 (q,J=6.7 Hz, 2H), 2.25 (s, 3H), 1.64 (quin, J=7.0 Hz, 2H), 1.35 (s, 9H)

LR MS (ES+): 634 (MNa+)

LR MS (ES−): 610 (M−H)

Example 45

N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of tert-butyl{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate(300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml oftrifluoroacetic acid. The mixture was stirred at room temperature for 10minutes and evaporated to dryness under reduced pressure. The residuewas re-dissolved in MeOH (5 ml) and poured into 100 ml of water withvigorous stirring. Saturated NaHCO₃ solution was added until pH=8˜9. Theprecipitates were filtered, washed with water and dried in vacuo to giveN-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideas yellow solid. Yield: 250 mg, 100%.

LR MS (ES+): 512 (MNa+)

LR MS (ES−): 510 (M−H)

Example 46

(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid

To a stirred suspension of tert-butyl(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate(70 mg, 0.10 mmol) in 5 ml of methylene chloride was added 2 ml oftrifluoroacetic acid. The mixture was stirred at room temperature for 2hours and evaporated to dryness under reduced pressure. The residue wasre-dissolved in MeOH (5 ml) and poured into 100 ml of water withvigorous stirring. The precipitates were filtered, washed with water anddried in vacuo to give(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid as light yellow solid. Yield: 53 mg, 83%.

¹H NMR (DMSO-d₆): 12.12 (br. s., 1H), 9.10 (d, J=2.3 Hz, 1H), 8.94-8.98(m, 2H), 8.59 (d, J=5.6 Hz, 1H), 8.42 (s, 1H), 8.26 (t, J=9.1 Hz, 1H),8.04 (t, J=5.6 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.40 (dd, J=11.7,2.6 Hz, 1H), 7.07-7.13 (m, 2H), 6.79-6.81 (m, 1H), 6.77-6.81 (m, 1H),4.34-4.42 (m, 1H), 3.02-3.13 (m, 2H), 2.29 (td, J=9.4, 6.2 Hz, 2H), 2.25(s, 3H), 1.97-2.09 (m, 1H), 1.84-1.95 (m, 1H), 1.00 (t, J=7.2 Hz, 3H)

LR MS (ES−): 610 (M−H)

Example 47

tert-butyl(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate

To a stirred suspension of(2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid (100 mg, 0.16 mmol) in 10 ml of anhydrous tetrahydrofuran wereadded HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (62 mg, 0.48mmol). The mixture was heated at 60° C. for 10 minutes, followed byaddition of 2M ethylamine solution in THF (0.25 ml, 0.50 mmol). Themixture was heated at 60° C. for another 5 minutes, cooled to roomtemperature and poured into 100 ml of water with vigorous stirring. 1MHCl was added dropwise until pH=4. The precipitates were filtered,washed with water and dried in vacuo to give the crude, which waspurified by silica gel chromatography eluting with 3˜5% methanol inchloroform to give tert-butyl(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoateas white solid. Yield: 73 mg, 70%.

¹H NMR (DMSO-d₆): 9.10 (d, J=2.3 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H), 8.93(d, J=7.9 Hz, 1H), 8.58 (d, J=5.6 Hz, 1H), 8.42 (s, 1H), 8.26 (t, J=9.1Hz, 1H), 8.02 (t, J=5.6 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.39 (dd,J=11.7, 2.6 Hz, 1H), 7.11 (ddd, J=9.0, 2.7, 1.2 Hz, 1H), 7.09 (dd, 1H),6.79 (d, J=5.6 Hz, 1H), 6.78-6.81 (m, 1H), 4.32-4.43 (m, 1H), 3.02-3.14(m, 2H), 2.26-2.30 (m, 2H), 2.25 (s, 3H), 1.97-2.05 (m, 1H), 1.83-1.92(m, 1H), 1.36 (s, 9H), 1.00 (t, J=7.2 Hz, 3H)

LR MS (ES+): 690 (MNa+)

LR MS (ES−): 666 (M−H)

Example 48

(2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid

To a stirred solution of 5-tert-butyl 1-methyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate(260 mg, 0.40 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1MNaOH solution (2 ml, 2 mmol). The mixture was stirred at roomtemperature for 1 hour and poured into 100 ml of water. 1M HCl was addedwith stirring until pH=4. The precipitates were filtered, washed withwater and dried in vacuo to give(2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid as off-white solid. Yield: 230 mg, 91%.

¹H NMR (DMSO-d₆): 12.81 (br. s., 1H), 9.11 (d, J=2.3 Hz, 1H), 9.07 (d,J=7.9 Hz, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.58 (d, J=5.3 Hz, 1H), 8.38 (s,1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.40 (dd,J=11.6, 2.8 Hz, 1H), 7.11-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H),6.79 (d, J=5.3 Hz, 1H), 6.78-6.82 (m, 1H), 4.40 (ddd, J=9.8, 7.7, 4.8Hz, 1H), 2.33-2.37 (m, 2H), 2.25 (s, 3H), 2.04-2.13 (m, 1H), 1.89-2.00(m, 1H), 1.36 (s, 9H)

LR MS (ES−): 639 (M−H)

The following Example 49 was prepared using the experiment proceduredescribed in Example 54, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 49

5-tert-butyl 1-methyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate

¹H NMR (DMSO-d₆): 9.18 (d, J=7.6 Hz, 1H), 9.10 (d, J=2.3 Hz, 1H), 8.96(d, J=2.3 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.26 (t, J=9.1Hz, 1H), 7.98 (dd, J=7.9, 1.8 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H),7.10-7.13 (m, 1H), 7.09 (dd, J=11.2, 8.2 Hz, 1H), 6.80 (d, J=5.6 Hz,1H), 6.78-6.81 (m, 1H), 4.48 (ddd, J=9.4, 7.3, 5.3 Hz, 1H), 3.65 (s,3H), 2.36 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 2.03-2.12 (m, 1H), 1.92-2.01(m, 1H), 1.37 (s, 9H)

LR MS (ES+): 677 (MNa+)

LR MS (ES−): 653 (M−H)

Example 50

1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylicacid

To a stirred solution of tert-butyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate(40 mg, 0.060 mmol) in 5 ml of methylene chloride was added 2 ml oftrifluoroacetic acid. The mixture was stirred at room temperature for 2hours, and evaporated to dryness under reduced pressure. 5 ml of waterwas added to the residue, and the mixture was neutralized to pH=7 withsaturated NaHCO₃ solution with vigorous stirring. The precipitates werefiltered, washed with 5 ml of water, and dried in vacuo to give1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylicacid as light brown solid. Yield: 37 mg, 100%.

LR MS (ES+): 610 (MH⁺)

LR MS (ES−): 608 (M−H)

The following Example 51 was prepared using the experiment proceduredescribed in Example 42, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 51

tert-butyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate

LR MS (ES+): 688 (MNa+)

LR MS (ES−): 664 (M−H)

Example 52

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide

To a stirred solution ofN-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide(1.23 g, 2.11 mmol) in 20 ml of tetrahydrofuran was added 2 ml of 2M HCl(4.0 mmol). The mixture was stirred at room temperature for 5 hours andpoured into 100 ml of water. 1M NaOH solution was added slowly untilpH=7˜8. The precipitates were filtered, washed with water and dried invacuo to give7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamideas brown solid. Yield: 1.07 g, 100%.

¹H NMR (DMSO-d₆): 9.69 (t, J=1.6 Hz, 1H), 9.10 (d, J=2.3 Hz, 1H),9.00-9.04 (m, 1H), 8.97 (d, J=2.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26(t, J=9.1 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.39 (dd,J=11.6, 2.8 Hz, 1H), 7.07-7.13 (m, 2H), 6.78-6.81 (m, 1H), 6.77 (d,J=5.6 Hz, 1H), 3.52-3.60 (m, 2H), 2.73 (td, J=6.7, 1.6 Hz, 2H), 2.25 (s,3H).

LR MS (ES+): 533 (MNa+)

LR MS (ES−): 509 (M−H)

Example 53

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide

To a stirred suspension of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (1.00 g, 2.20 mmol) in 20 ml of anhydrous THF were added HATU (1.04g, 2.74 mmol) and N,N-diisopropylethylamine (636 mg, 4.93 mmol). Themixture was heated at 60° C. for 15 minutes, followed by addition of3-aminopropanol (248 mg, 3.3 mmol). The mixture was stirred for another10 minutes, cooled to room temperature and poured into 100 ml of waterwith vigorous stirring. 2M HCl was added dropwise until pH=4. Theprecipitates were filtered, washed with water and dried in vacuo to give7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamideas white solid. Yield: 1.12 g, 100%.

¹H NMR (DMSO-d₆): 9.10 (s, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.91 (t, J=5.4Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 8.26 (t, J=9.0 Hz, 1H), 8.22 (s, 1H),7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.40 (dd, J=11.4, 2.6 Hz, 1H), 7.06-7.14(m, 2H), 6.79-6.82 (m, 1H), 6.78 (d, J=5.6 Hz, 1H), 3.46 (t, J=6.2 Hz,2H), 3.33 (q, J=6.6 Hz, 2H), 2.25 (s, 3H), 1.69 (quin, J=6.7 Hz, 2H)

LR MS (ES+): 535 (MNa+)

LR MS (ES−): 511 (M−H)

Example 54

dimethyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate

To a stirred suspension of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (100 mg, 0.22 mmol) in 10 ml of anhydrous tetrahydrofuran wereadded HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg,0.66 mmol). The mixture was heated at 60° C. for 10 minutes, followed byaddition of L-glutamic acid dimethyl ester hydrochloride (55 mg, 0.26mmol). The mixture was heated at 60° C. for another 20 minutes, cooledto room temperature and poured into 100 ml of water with vigorousstirring. 1M HCl was added dropwise until pH=4. The precipitates werefiltered, washed with water and dried in vacuo to give dimethyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioateas white solid. Yield: 126 mg, 94%.

¹H NMR (DMSO-d₆): 9.21 (d, J=7.3 Hz, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.96(d, J=2.3 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.37 (s, 1H), 8.26 (t, J=9.1Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H),7.06-7.15 (m, 2H), 6.77-6.82 (m, 2H), 4.48 (ddd, J=9.4, 7.3, 5.3 Hz,1H), 3.65 (s, 3H), 3.57 (s, 3H), 2.45-2.49 (m, 2H), 2.25 (s, 3H),2.09-2.18 (m, 1H), 1.97-2.07 (m, 1H)

LR MS (ES+): 635 (MNa+)

LR MS (ES−): 611 (M−H)

The following Example 55 was prepared using the experiment proceduredescribed in Example 34, but with the appropriate reagent, reactionconditions and reactant substitutions that will be readily realized bythose of ordinary skill in this art without the exercise of undueexperimentation.

Example 55

7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-morpholin-4-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (DMSO-d₆): 9.12 (d, J=1.8 Hz, 1H), 8.98 (d, J=2.3 Hz, 1H), 8.93(t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.22(s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H),7.06-7.13 (m, 2H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.54 (t,J=4.5 Hz, 4H), 3.31 (q, J=6.75 Hz, 2H), 2.29-2.37 (m, 6H), 2.25 (s, 3H),1.69 (quin, J=7.0 Hz, 2H)

LR MS (ES+): 582 (MH⁺)

LR MS (ES−): 580 (M−H)

Example 56

ethyl4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate

To a stirred suspension of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.27 mmol) in 10 ml of anhydrous THF were added HATU (122mg, 0.32 mmol) and N,N-diisopropylethylamine (104 mg, 0.81 mmol). Themixture was heated at 60° C. for 5 minutes, followed by addition ofethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture wasstirred for another 10 minutes, cooled to room temperature and pouredinto 100 ml of water with vigorous stirring. 1M HCl was added dropwiseuntil pH=5. The precipitates were filtered, washed with water and driedin vacuo to give ethyl4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoateas white solid. Yield: 150 mg, 99%.

¹H NMR (DMSO-d₆): 9.19 (s, 1H), 8.92 (t, J=5.7 Hz, 1H), 8.54 (d, J=5.3Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.21 (s, 1H), 7.94-7.98 (m, 1H),7.53-7.58 (m, 2H), 7.20-7.25 (m, 2H), 7.08 (dd, J=11.3, 8.4 Hz, 1H),6.76-6.81 (m, 1H), 6.69 (d, J=5.6 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H),3.28-3.32 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 1.79 (quin,J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H)

LR MS (ES+): 573 (MNa+)

LR MS (ES−): 549 (M−H)

Example 57

ethyl4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate

To a stirred suspension of7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.26 mmol) in 10 ml of anhydrous THF were added HATU (118mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). Themixture was heated at 60° C. for 5 minutes, followed by addition ofethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture wasstirred for another 10 minutes, cooled to room temperature and pouredinto 100 ml of water with vigorous stirring. 1M HCl was added dropwiseuntil pH=5. The precipitates were filtered, washed with water and driedin vacuo to give ethyl4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl)}carbonyl)amino]butanoateas white solid. Yield: 150 mg, 100%.

¹H NMR (DMSO-d₆): 9.10 (d, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.93 (t, J=5.7Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.22 (s, 1H),7.98 (dd, J=8.2, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H), 7.10-7.13(m, 1H), 7.09 (dd, J=11.2, 8.2 Hz, 1H), 6.78-6.81 (m, 1H), 6.78 (d,J=5.6 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.27-3.32 (m, 2H), 2.36 (t, J=7.3Hz, 2H), 2.25 (s, 3H), 1.79 (quin, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H)

LR MS (ES+): 591 (MNa+)

LR MS (ES−): 567 (M−H)

Example 58

N-[dimethyl(oxido)-lambda˜4˜sulfanylidene]-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-carboxamideExample 59

4-[N-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoicacid Example 60

4-[N-({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoicacid Example 61

N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamideExample 62

[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]aceticacid Example 63

[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]aceticacid Example 64

4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoicacid

To a stirred solution of ethyl4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate(110 mg, 0.19 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0mmol). The mixture was heated at 60° C. for 2 hours, cooled to roomtemperature and poured into 100 ml of water with vigorous stirring. 2MHCl was added dropwise until pH=4. The precipitates were filtered,washed with water and dried in vacuo to give4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoicacid as white solid. Yield: 95 mg, 90%.

¹H NMR (DMSO-d₆): 12.07 (br. s., 1H), 9.11 (d, J=2.3 Hz, 1H), 8.97 (d,J=2.3 Hz, 1H), 8.94 (t, J=5.6 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.26 (t,J=9.1 Hz, 1H), 8.23 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.40 (dd,J=11.6, 2.8 Hz, 1H), 7.11-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H),6.79-6.81 (m, 1H), 6.78 (d, J=5.3 Hz, 1H), 3.26-3.33 (m, 2H), 2.29 (t,J=7.3 Hz, 2H), 2.25 (s, 3H), 1.77 (quin, J=7.1 Hz, 2H)

LR MS (ES+): 541 (MH⁺)

LR MS (ES−): 539 (M−H)

Example 65

4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoicacid

To a stirred solution of ethyl4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate(110 mg, 0.20 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0mmol). The mixture was heated at 60° C. for 3 hours, cooled to roomtemperature and poured into 100 ml of water with vigorous stirring. 2MHCl was added dropwise until pH=4. The precipitates were filtered,washed with water and dried in vacuo to give4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoicacid as white solid. Yield: 100 mg, 96%.

¹H NMR (DMSO-d₆): 12.06 (s, 1H), 9.19 (s, 1H), 8.91 (t, J=5.7 Hz, 1H),8.54 (d, J=5.3 Hz, 1H), 8.47 (d, J=2.9 Hz, 1H), 8.21 (s, 1H), 7.96 (dd,J=7.9, 2.3 Hz, 1H), 7.54-7.58 (m, 2H), 7.20-7.24 (m, 2H), 7.08 (dd,J=11.3, 8.4 Hz, 1H), 6.76-6.81 (m, 1H), 6.68 (d, J=5.3 Hz, 1H),3.27-3.31 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.76 (quin,J=7.2 Hz, 2H)

LR MS (ES+): 545 (MNa+)

LR MS (ES−): 521 (M−H)

Example 66

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide

To a stirred, cooled (0° C.) solution of7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.27 mmol) in anhydrous DMF (10 ml) were added PyBOP (156mg, 0.30 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). Themixture was stirred at 0° C. for 5 minutes, followed by addition ofN-(3-aminopropyl)piperidine (58 mg, 0.41 mmol). Stirring was continuedat 0° C. for another 30 minutes. The mixture was poured into 100 ml ofwater with vigorous stirring. The precipitates were filtered, washedwith water and dried to give7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamideas beige solid. Yield: 151 mg, 98%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.21 (s, 1H) 8.94 (t, J=5.58 Hz, 1H)8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.22 (s, 1H) 7.98 (dd,J=7.63, 2.05 Hz, 1H) 7.57-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd,J=11.30, 8.36 Hz, 1H) 6.80-6.83 (m, 1H) 6.71 (d, J=5.28 Hz, 1H)3.30-3.35 (m, 2H) 2.31 (br. s., 6H) 2.28 (s, 3H) 1.69-1.75 (m, 2H)1.47-1.52 (m, 4H) 1.38 (br. s., 2H)

LR MS (ES+): 584 (M+Na⁺)

LR MS (ES−): 560 (M−H)

Example 67

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide

The above compound was prepared using procedures similar to that used toprepare the compound of Example 66 above.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.47 (s, 1H) 8.97 (t, J=5.58 Hz, 1H)8.62 (d, J=2.35 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.24 (s, 1H) 7.97 (dd,J=7.78, 1.91 Hz, 1H) 7.58-7.61 (m, 2H) 7.23-7.26 (m, 2H) 7.10 (dd,J=11.30, 8.36 Hz, 1H) 6.79-6.82 (m, 1H) 6.71 (d, J=5.28 Hz, 1H)3.32-3.34 (m, 2H) 2.34-2.47 (m, 10H) 2.27 (s, 3H) 2.21 (s, 3H) 1.72(quin, J=6.97 Hz, 2H).

LR MS (ES+): 577 (MH⁺)

Example 68

7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide

The above compound was prepared using procedures similar to that used toprepare the compound of Example 66 above.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H) 8.99 (t, J=5.27 Hz, 1H)8.57 (d, J=5.27 Hz, 1H) 8.51 (d, J=2.05 Hz, 1H) 8.21 (s, 1H) 7.98 (dd,J=7.77, 1.90 Hz, 1H) 7.55-7.61 (m, 2H) 7.22-7.28 (m, 2H) 7.11 (dd,J=11.43, 8.20 Hz, 1H) 6.78-6.85 (m, 1H) 6.72 (d, J=5.27 Hz, 1H)3.32-3.39 (m, 2H) 2.56 (br. s., 6H) 2.28 (s, 3H) 1.76 (m, J=8.79 Hz, 6H)

LR MS (ES+): 548 (MH⁺)

LR MS (ES−): 546 (M−H)

Example 69

N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

The above compound was prepared using procedures similar to that used toprepare the compound of Example 66 above.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.21 (s, 1H) 8.88 (t, J=5.13 Hz, 1H)8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.21 (s, 1H) 7.98 (dd,J=7.92, 2.05 Hz, 1H) 7.56-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd,J=11.30, 8.36 Hz, 1H) 6.79-6.82 (m, 1H) 6.71 (d, J=5.28 Hz, 1H)3.33-3.37 (m, 2H) 2.58 (t, J=7.04 Hz, 2H) 2.50-2.54 (m, 4H) 2.27 (s, 3H)0.97 (t, J=7.04 Hz, 6H)

LR MS (ES+): 536 (MH⁺)

LR MS (ES−): 534 (M−H)

Example 70

N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide

The above compound was prepared using procedures similar to that used toprepare the compound of Example 66 above.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.25 (s, 1H) 8.96 (br. s., 1H) 8.57 (d,J=5.28 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H) 8.21 (s, 1H) 7.98 (dd, J=7.48,1.91 Hz, 1H) 7.57-7.61 (m, 2H) 7.23-7.26 (m, 2H) 7.11 (dd, J=11.30, 8.36Hz, 1H) 6.80-6.83 (m, 1H) 6.72 (d, J=5.28 Hz, 1H) 3.32-3.35 (m, 2H)2.38-2.49 (m, 6H) 2.28 (s, 3H) 1.70 (br. s., 2H) 0.97 (br. s., 6H)

LR MS (ES+): 550 (MH⁺)

LR MS (ES−): 548 (M−H)

Example 71

Methyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate

Step 1: A mixture of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate(500 mg, 2.20 mmol), 3-aminophenol (330 mg, 3.0 mmol), ethyl2-cyclohexanonecarboxylate (73 mg, 0.43 mmol), copper(I) chloride (22mg, 0.22 mmol) and cesium carbonate (1.48 g, 4.55 mmol) in 20 ml ofanhydrous DMSO was placed in a 50 ml pressure tube, flushed withnitrogen, sealed and heated at 70° C. for 3 hours. The mixture wascooled to room temperature and poured into 100 ml of water. Theprecipitates were filtered, washed with water and dried to give crudemethyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate as brownsolid. Yield: 330 mg.

Step 2: To a stirred solution of 3-methyl-2-furoic acid (166 mg, 1.32mmol) in anhydrous DMF (10 ml) were added HATU (552 mg, 1.45 mmol) andDIPEA (341 mg, 2.64 mmol). The mixture was stirred at room temperaturefor 10 minutes, and 330 mg of crude methyl7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate from step 1 wasadded. The mixture was then heated at 65° C. for 2 hours, cooled to roomtemperature, and poured into 100 ml of water. 2M HCl was added untilpH=4. The precipitates were filtered, washed with water and dried togive the crude, which was purified by silica gel chromatography elutingwith 2˜3% of MeOH in chloroform to afford methyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylateas off-white solid. Yield: 230 mg, 26% for 2 steps.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H) 8.67 (d, J=5.27 Hz, 1H)8.25 (s, 1H) 7.82 (t, J=2.05 Hz, 1H) 7.80 (dd, J=1.76, 0.59 Hz, 1H) 7.76(ddd, J=8.21, 2.05, 0.88 Hz, 1H) 7.48 (t, J=8.06 Hz, 1H) 7.05 (ddd,J=8.06, 2.49, 0.88 Hz, 1H) 6.90 (d, J=5.27 Hz, 1H) 6.60 (d, J=2.05 Hz,1H) 3.93 (s, 3H) 2.32 (s, 3H)

LR MS (ES+): 431 (M+Na⁺)

LR MS (ES−): 407 (M−H)

Example 72

7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid

To a stirred solution of methyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate(180 mg, 0.44 mmol) in MeOH (10 ml) was added 1M NaOH (1.5 ml, 1.5mmol). The mixture was stirred at room temperature for 1 hour, andpoured into 100 ml of water. 2M HCl was added until pH=4. Theprecipitates was filtered, washed with water and dried to give7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid as off-white solid. Yield: 160 mg, ˜92%.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.26 (s, 1H) 8.65 (d, J=5.27 Hz, 1H)8.14 (s, 1H) 7.81 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.47 Hz, 1H) 7.76 (ddd,J=8.21, 2.05, 0.88 Hz, 1H) 7.47 (t, J=8.20 Hz, 1H) 7.04 (ddd, J=8.21,2.34, 0.88 Hz, 1H) 6.87 (d, J=5.57 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 2.32(s, 3H).

Example 73

N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide

To a stirred, cooled (0° C.) solution of7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added PyBOP (171mg, 0.33 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). Themixture was stirred at 0° C. for 5 minutes, followed by addition of 2Methylamine solution in THF (0.18 ml, 0.36 mmol). Stirring was continuedat 0° C. for another 40 minutes. The mixture was poured into 100 ml ofwater with vigorous stirring. 2M HCl was added dropwise until pH=5. Theprecipitates were filtered, washed with water and dried to giveN-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamideas light yellow solid. Yield: 115 mg, 90%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.94 (t, J=5.43 Hz, 1H)8.60 (d, J=5.28 Hz, 1H) 8.24 (s, 1H) 7.79-7.80 (m, 2H) 7.75 (ddd,J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14,2.42, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (dd, J=1.76, 0.59 Hz,1H) 3.32-3.36 (m, 2H) 2.32 (s, 3H) 1.17 (t, J=7.34 Hz, 3H)

LR MS (ES+): 444 (M+Na⁺)

LR MS (ES−): 420 (M−H)

The compounds of Examples 74-78 below were prepared using proceduressimilar to those of Example 73.

Example 74

N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.26 (s, 1H) 8.61 (d, J=5.58 Hz, 1H)7.81 (t, J=2.20 Hz, 1H) 7.79-7.80 (m, 2H) 7.75 (ddd, J=8.22, 2.05, 0.88Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.03 (ddd, J=8.07, 2.49, 0.88 Hz, 1H)6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 3.51 (br. s., 4H) 2.32(s, 3H) 1.20 (br. s., 6H)

LR MS (ES+): 472 (M+Na⁺)

LR MS (ES−): 448 (M−H)

Example 75

N-hydroxy-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ ppm 11.70 (s, 1H) 10.26 (s, 1H) 9.45 (s, 1H)8.60 (d, J=5.28 Hz, 1H) 8.09 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd,J=8.29, 1.98, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.07,2.49, 0.88 Hz, 1H) 6.82 (d, J=5.58 Hz, 1H) 6.59 (dd, J=1.76, 0.59 Hz,1H) 2.32 (s, 3H)

LR MS (ES+): 431 (M+Na⁺)

LR MS (ES−): 408 (M−H)

Example 76

N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.92 (t, J=5.58 Hz, 1H)8.60 (d, J=5.28 Hz, 1H) 8.25 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd,J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14,2.42, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 4.50(t, J=5.28 Hz, 1H) 3.46-3.51 (m, 2H) 3.33-3.38 (m, 2H) 2.32 (s, 3H)1.68-1.76 (m, 2H)

LR MS (ES+): 474 (M+Na⁺)

LR MS (ES−): 450 (M−H)

Example 77

N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.97 (t, J=5.72 Hz, 1H)8.60 (d, J=5.28 Hz, 1H) 8.28 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd,J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.22,2.35, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.47 Hz, 1H) 4.81(t, J=5.58 Hz, 1H) 3.55 (q, J=5.97 Hz, 2H) 3.37 (q, J=6.06 Hz, 2H) 2.32(s, 3H)

LR MS (ES+): 460 (M+Na⁺)

LR MS (ES−): 436 (M−H)

Example 78

7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 9.13 (t, J=5.57 Hz, 1H)8.61 (d, J=5.57 Hz, 1H) 8.20 (s, 1H) 7.78-7.81 (m, 2H) 7.75 (d, J=8.20Hz, 1H) 7.46 (t, J=8.06 Hz, 1H) 7.02 (ddd, J=8.13, 2.42, 0.88 Hz, 1H)6.83 (d, J=5.27 Hz, 1H) 6.59 (d, J=1.47 Hz, 1H) 3.63-3.70 (m, 2H) 3.17(t, J=7.03 Hz, 2H) 2.32 (s, 3H)

LR MS (ES+): 490 (MH⁺)

LR MS (ES−): 488 (M−H)

Example 79

3-hydroxypropyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate

To a stirred solution of7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added3-bromo-1-propanol (63 mg, 0.45 mmol) and potassium carbonate (83 mg,0.60 mmol). The mixture was heated at 50° C. for 5 hours and poured into100 ml of water. The precipitates were filtered, washed with water anddried to give the crude, which was purified by silica gel chromatographyeluting with 3˜5% of methanol in chloroform to give 3-hydroxypropyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylateas white solid. Yield: 25 mg, 18%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H) 8.67 (d, J=5.28 Hz, 1H)8.24 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.47 Hz, 1H) 7.76 (dt,J=9.24, 0.95 Hz, 1H) 7.48 (t, J=8.22 Hz, 1H) 7.04 (ddd, J=8.07, 2.49,0.88 Hz, 1H) 6.89 (d, J=5.28 Hz, 1H) 6.60 (d, J=1.47 Hz, 1H) 4.61 (t,J=5.14 Hz, 1H) 4.42 (t, J=6.60 Hz, 2H) 3.55-3.59 (m, 2H) 2.32 (s, 3H)1.88 (quin, J=6.31 Hz, 2H)

LR MS (ES+): 475 (M+Na⁺)

LR MS (ES−): 451 (M−H)

The compounds of Examples 80-81 below were prepared using proceduressimilar to those of Example 79.

Example 80

2-hydroxyethyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H) 8.68 (d, J=5.58 Hz, 1H)8.29 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.17 Hz, 1H) 7.76 (ddd,J=8.36, 1.91, 0.88 Hz, 1H) 7.48 (t, J=8.22 Hz, 1H) 7.05 (ddd, J=8.22,2.35, 0.88 Hz, 1H) 6.89 (d, J=5.58 Hz, 1H) 6.59-6.60 (m, 1H) 4.99 (t,J=5.72 Hz, 1H) 4.36 (dd, J=5.43, 4.55 Hz, 2H) 3.71-3.75 (m, 2H) 2.32 (s,3H)

LR MS (ES+): 461 (M+Na⁺)

LR MS (ES−): 437 (M−H)

Example 81

2-methoxyethyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate

¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H) 8.68 (d, J=5.27 Hz, 1H)8.24 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.17 Hz, 1H) 7.76 (ddd,J=8.20, 2.05, 0.88 Hz, 1H) 7.47 (t, J=8.20 Hz, 1H) 7.05 (ddd, J=8.13,2.42, 0.88 Hz, 1H) 6.90 (d, J=5.27 Hz, 1H) 6.60 (d, J=1.47 Hz, 1H)4.46-4.50 (m, 2H) 3.66-3.71 (m, 2H) 3.33 (s, 3H) 2.32 (s, 3H)

LR MS (ES+): 453 (MH⁺)

LR MS (ES−): 451 (M−H)

Example 82

Methyl[(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate

To a stirred, cooled (0° C.) solution of7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid (150 mg, 0.38 mmol) in anhydrous DMF (10 ml) were added PyBOP (218mg, 0.42 mmol) and N,N-diisopropylethylamine (245 mg, 1.9 mmol). Themixture was stirred at 0° C. for 10 minutes, followed by addition ofmethyl [(3-aminopropyl)amino]acetate dihydrochloride (100 mg, 0.46mmol). Stirring was continued at 0° C. for another 40 minutes. Themixture was diluted with ethyl acetate (100 ml), washed with brine(4×100 ml), dried over Na₂SO₄, and concentrated to give the crude, whichwas purified by silica gel chromatography eluting with 5-8% methanol inchloroform to give methyl[(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetateas light beige solid. Yield: 98 mg, 49%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.95 (t, J=5.58 Hz, 1H)8.60 (d, J=5.58 Hz, 1H) 8.23 (s, 1H) 7.79-7.80 (m, 2H) 7.73-7.76 (m, 1H)7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14, 2.42, 0.88 Hz, 1H) 6.82 (d,J=5.58 Hz, 1H) 6.59 (d, J=1.17 Hz, 1H) 3.62 (s, 3H) 3.32-3.36 (m, 4H)2.58 (t, J=6.75 Hz, 2H) 2.32 (s, 3H) 2.05 (br. s., 1H) 1.68 (quin,J=6.90 Hz, 2H)

LR MS (ES+): 545 (M+Na⁺)

LR MS (ES−): 521 (M−H)

Example 82A

N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide

Step 1: To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) andDIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperaturefor 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled toroom temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl(200 ml). The organic phase was washed with 0.5M HCl (2×50 ml),saturated NaHCO₃ (50 ml) and brine (50 ml), dried over Na₂SO₄, andevaporated to dryness to afford3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide as light brown solid.Yield: 1.5 g, 100%.

Step 2: A solution of 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide(1.5 g, 4.48 mmol from Step 1) in 20 ml of MeOH containing 10% Pd/C (150mg) was stirred under a hydrogen balloon at room temperature for 2hours. The catalyst was removed by filtration. The filtrate solution wasevaporated to dryness under reduced pressure to giveN-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide as light-beige solid.Yield: 1.1 g, 100%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.92 (s, 1H) 9.75 (br. s., 1H) 7.37-7.40(m, 2H) 7.33 (t, J=2.05 Hz, 1H) 7.31 (t, J=7.78 Hz, 1H) 7.15 (dd,J=10.56, 8.51 Hz, 1H) 7.03-7.07 (m, 1H) 6.96-6.99 (m, 1H) 2.30 (s, 3H)

LR MS (ES+): 268 (M+Na⁺)

LR MS (ES−): 244 (M−H)

Example 83

Methyl7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate

A mixture of N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide (270 mg, 1.1mmol), methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (300 mg, 1.3mmol) and cesium carbonate (1.0 g, 3.07 mmol) in 10 ml of anhydrous DMSOwas heated at 68° C. for 16 hours, cooled to room temperature andpartitioned between water (100 ml) and EtOAc (100 ml). The aqueous layerwas extracted with more EtOAc (2×50 ml). All the organic layers werecombined, washed with brine (50 ml), dried over Na₂SO₄, and evaporatedto dryness to give the crude, which was purified by silica gelchromatography eluted with 1˜2% of MeOH in CHCl₃ to give methyl7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylateas light brown oil. Yield: 170 mg, 37%.

Example 84

7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylicacid

To a stirred solution of methyl7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate(170 mg, 0.39 mmol) in 15 ml of MeOH was added 1 ml of 1M NaOH. Reactionwas complete within 2.5 hours. The mixture was poured into 100 ml ofwater and acidified with 2M HCl to pH=5 with vigorous stirring. Theprecipitates were filtered, washed with water and dried in vacuo to give7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylicacid as white solid. Yield: 150 mg, 91%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 13.96 (br. s., 1H) 10.15 (s, 1H) 8.66(d, J=4.40 Hz, 1H) 8.15 (s, 1H) 7.97 (d, J=7.92 Hz, 1H) 7.90 (s, 1H)7.70 (t, J=7.92 Hz, 1H) 7.60 (dd, J=8.07, 1.61 Hz, 1H) 7.38 (dd, J=7.34,1.76 Hz, 1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H) 7.04-7.09 (m, 1H) 6.87 (d,J=5.28 Hz, 1H) 2.29 (s, 3H)

LR MS (ES+): 423 (MH⁺)

LR MS (ES−): 421 (M−H)

Example 85

N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide

To a stirred, cooled (0° C.) solution of7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylicacid (120 mg, 0.28 mmol) in anhydrous DMF (10 ml) were added PyBOP (161mg, 0.31 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol). Themixture was stirred at 0° C. for 5 minutes, followed by addition of 2Methylamine solution in THF (0.2 ml, 0.4 mmol). Stirring was continued at0° C. for another 30 minutes. The mixture was poured into 100 ml ofwater with vigorous stirring. 2M HCl was added dropwise until pH=4. Theprecipitates were filtered, washed with water and dried to giveN-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamideas yellow solid. Yield: 112 mg, 88%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.15 (s, 1H) 8.96 (t, J=5.58 Hz, 1H)8.62 (d, J=5.58 Hz, 1H) 8.26 (s, 1H) 7.96 (dd, J=7.78, 1.03 Hz, 1H)7.87-7.89 (m, 1H) 7.69 (t, J=7.92 Hz, 1H) 7.58 (ddd, J=8.14, 2.57, 1.03Hz, 1H) 7.38 (dd, J=7.34, 1.76 Hz, 1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H)7.05-7.09 (m, 1H) 6.83 (d, J=5.58 Hz, 1H) 3.34 (qd, J=7.24, 5.58 Hz, 2H)2.29 (s, 3H) 1.17 (t, J=7.34 Hz, 3H)

LR MS (ES+): 472 (M+Na⁺)

LR MS (ES−): 448 (M−H)

The compound of Examples 86 below was prepared using procedures similarto those used to prepare the compound of Example 85.

Example 86

N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.15 (s, 1H) 8.62 (d, J=5.28 Hz, 1H)7.97 (d, J=7.92 Hz, 1H) 7.89-7.90 (m, 1H) 7.82 (s, 1H) 7.69 (t, J=7.92Hz, 1H) 7.58 (ddd, J=8.07, 2.49, 1.17 Hz, 1H) 7.38 (dd, J=7.19, 1.91 Hz,1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H) 7.07 (td, J=5.21, 2.49 Hz, 1H) 6.83(d, J=5.58 Hz, 1H) 3.52 (br. s., 4H) 2.29 (s, 3H) 1.21 (br. s., 6H)

LR MS (ES+): 500 (M+Na⁺)

LR MS (ES−): 476 (M−H)

Example 87

Methyl{[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate

To a stirred, cooled (0° C.) solution of7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylicacid (80 mg, 0.19 mmol) in anhydrous DMF (10 ml) were added PyBOP (109mg, 0.21 mmol) and N,N-diisopropylethylamine (123 mg, 0.95 mmol). Themixture was stirred at 0° C. for 10 minutes, followed by addition ofmethyl [(3-aminopropyl)amino]acetate dihydrochloride (50 mg, 0.23 mmol).Stirring was continued at 0° C. for 10 minutes then room temperature for2 hours. The mixture was poured into 100 ml of water with vigorousstirring. The precipitates were filtered, washed with water and dried togive the crude, which was purified by silica gel chromatography elutingwith 5-8% methanol in chloroform to give methyl{[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetateas light beige solid. Yield: 40 mg, 38%.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.15 (s, 1H) 8.97 (t, J=5.58 Hz, 1H)8.62 (d, J=5.28 Hz, 1H) 8.25 (s, 1H) 7.96 (dt, J=7.70, 1.28 Hz, 1H)7.87-7.89 (m, 1H) 7.69 (t, J=7.92 Hz, 1H) 7.58 (ddd, J=8.14, 2.42, 0.88Hz, 1H) 7.38 (dd, J=7.19, 1.91 Hz, 1H) 7.16 (dd, J=10.56, 8.51 Hz, 1H)7.05-7.08 (m, 1H) 6.83 (d, J=5.28 Hz, 1H) 3.62 (s, 3H) 3.34-3.37 (m, 4H)2.59 (t, J=6.90 Hz, 2H) 2.29 (s, 3H) 1.68 (quin, J=6.97 Hz, 2H)

LR MS (ES+): 551 (MH⁺)

4. Biological Testing

Biological data for the compounds of the present invention was generatedby the use of one or more of the following assays.

VEGF Stimulated Ca.Sup.++ Signal In Vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of VEGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. HUVEC (humanumbilical vein endothelial cells) (Clonetics) were seeded in 96-wellfibronectin coated black-walled plates overnight at 37.degree. C./5%CO.sub.2. Cells were loaded with calcium indicator Fluo-4 for 45 minutesat 37.degree. C. Cells were washed 4 times (Original Cell Wash,Labsystems) to remove extracellular dye. Test compounds werereconstituted in 100% DMSO and added to the cells to give a final DMSOconcentration of 0.1%. For screening, cells were pre-incubated with testagents for 30 minutes, at a single concentration (10 .mu.M) or atconcentrations ranging from 0.01 to 10.0 .mu.M followed by VEGFstimulation (5 ng/mL). Changes in fluorescence at 516 nm were measuredsimultaneously in all 96 wells using a cooled CCD camera. Data weregenerated by determining max-min fluorescence levels for unstimulated,stimulated, and drug treated samples. IC.sub.50 values for testcompounds were calculated from % inhibition of VEGF stimulated responsesin the absence of inhibitor.

VEGFR2 Kinase Assay

The cytoplasmic domain of the human VEGF receptor (VEGFR-2) wasexpressed as a Histidine-tagged fusion protein following infection ofinsect cells using an His engineered baculovirus. His-VEGFR-2 waspurified to homogeneity, as determined by SDS-PAGE, using nickel resinchromatography. Kinase assays were performed in 96 well microtiterplates that were coated overnight with 30 .mu.g of poly-Glu-Tyr (4:1) in10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates wereincubated with 1% BSA and then washed four times with PBS prior tostarting the reaction. Reactions were carried out in 120 .mu.L reactionvolumes containing 3.6 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4).Test compounds were reconstituted in 100% DMSO and added to the reactionto give a final DMSO concentration of 5%. Reactions were initiated bythe addition 0.5 ng of purified protein. Following a ten minuteincubation at 25.degree. C., the reactions were washed four times withPBS containing 0.05% Tween-20.100 .mu.l of a monoclonalanti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000in PBS-Tween-20 and added to the wells for 30 minutes. Following fourwashes with PBS-Tween-20, 100 .mu.l of O-phenylenediamineDihydrochloride in Phosphate-citrate buffer, containing urea hydrogenperoxide, was added to the wells for 7 minutes as a colorimetricsubstrate for the peroxidase. The reaction was terminated by theaddition of 100 .mu.l of 2.5N H.sub.2 SO.sub.4 to each well and readusing a microplate ELISA reader set at 492 nm. IC.sub.50 values forcompound inhibition were calculated directly from graphs of opticaldensity (arbitrary units) versus compound concentration followingsubtraction of blank values.

VEGF-Induced Dermal Extravasation in Guinea Pig (Miles Assay)

Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane,sheared, and given a single dose of drug or the respective vehicle. Theguinea pigs were dosed orally unless indicated otherwise in Table 3. Tenminutes prior to the end of drug treatment, guinea pigs wereanesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS(13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes,triplicate intradermal injections of 100 ng rhVEGF.sub.165 in 100 .mu.lPBS and of 100 .mu.l PBS alone were administered on the flank. After 20minutes, each animal was cuthanized with Pentosol, and the skincontaining the intradermal injection sites was removed for imageanalysis. Using an analog video camera coupled to a PC, an image of eachtrans-illuminated skin sample was captured, and the integrated opticaldensity of each injection site was measured using ImagePro 4. For eachskin sample, the difference between the mean optical density of the VEGFsites and mean optical density of the PBS sites is the measure ofVEGF-induced EBD extravasation in that animal. These measured valueswere averaged per study group to determine the mean VEGF-induced EBDextravasation for each experimental condition, and the group means werethen compared to assess inhibition of VEGF-induced EBD extravasation inthe drug-treated groups relative to the vehicle-treated controls. Todetermine the dose required for 50% inhibition (ID.sub.50), the percentinhibition data was plotted as a function of oral dose, using the‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50 valuewas verified visually by using the plotted data (horizontal line from50% y value, at intersection with best-fit line drop vertical line to xaxis (dose).

Laser-Induced Choroidal Neovascularization (CNV) in Rat (CNV Assay)

CNV was induced and quantified in this model as previously described(Edelman and Castro. Exp. Eye Res. 2000; 71:523-533). On day 0, maleBrown Norway rats (200-300 g) were anesthetized with 100 mg/kg Ketamineand 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide.Using the blue-green setting of a Coherent Novus Argon Laser, 3 laserbums (90 mW for 0.1 s; 100 .mu.m diameter) were given to each eyebetween the retinal vessels around the optic nerve head. Rats were dosedwith test compounds in their indicated vehicles orally once daily.

On day 10, rats were sacrificed with 100% CO.sub.2, and blood vesselswere labeled by vascular perfusion with 10 mg/ml FITC-dextran (MW2.times. 10.sup.6). Using an epifluorescence microscope (20.times.)coupled to a spot digital camera and a PC, images were obtained from theflat mounts of the RPE-choroid-sclera from each eye, and the areaoccupied by hyperfluorescent neovessels within each laser lesion wasmeasured using ImagePro 4 software.

To determine the dose required for 50% inhibition (ID.sub.50), thepercent inhibition data was plotted as a function of oral dose, usingthe ‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50value was verified visually by using the plotted data (horizontal linefrom 50% y value, at intersection with best-fit line drop vertical lineto x axis (dose).

Rabbit Eye VEGF Permeability Model

Assay used was detailed by Jeffrey Edelman, etc in Exp. Eye. Res.80(2005), Pg 249-258.

PDGF Stimulated Ca²⁺ Signal in Vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of PDGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad(Normal human dermal fibroblasts) (Lonza) were seeded in 384-wellfibronectin coated black-walled plates overnight at 37° C./5% CO₂. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 4 times (ELx405-CW, Bio-Tek) to remove extracellular dye.Test compounds were reconstituted in 100% DMSO and added to the cells togive a final DMSO concentration of 0.1%. For screening, cells werepre-incubated with test agents for 30 minutes, at a single concentration(10 μM) or at concentrations ranging from 0.001 nM to 10 μM followed byPDGF stimulation (10 ng/mL). Changes in fluorescence at 515 nm weremeasured simultaneously in all 384 wells using a cooled CCD camera. Datawere generated by determining max-min fluorescence levels forunstimulated, stimulated, and drug treated samples. IC₅₀ values for testcompounds were calculated from % inhibition of PDGF stimulated responsesin the absence of inhibitor.

TABLE II Biological Activities of Compounds of the Present Invention InVivo Cellular Enzymic Enzymic Rabbit Eye VEGFR2 VEGFR2 VEGFR1 VEGFCompound IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) Permeability F1  2 18 F2 29 20 16efficacious F3 35 21 F4  10⁴  10⁴ F5  10⁴  10⁴ F6 11 F7 10 F8 11 In VivoCellular Enzymic Enzymic Enzymic Rabbit Eye VEGFR2 VEGFR2 VEGFR1 PDGFRβVEGF Example IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) Permeability 12 1263 4 20 13 97 6 10 19 14 34 4 5 13 15 39 3 3 10 16 7 10 15 17 4 10 15 180.8 3 6 11 Efficacious 19 0.3 4 9 14 23 9 7 13 14 24 14 10 9 14 25 5 811 26 5 10 12 27 16 11 17 28 5 8 17 29 5 10 13 30 7 112 17 31 9 9 13 324 11 15 33 24 60 69 34 3 6 11 36 7 8 37 1 7 9 38 14 7 8 39 2 5 8 42 4 643 6 3 44 16 11 45 10 7 46 328 19 Efficacious 48 7 50 80 16 18 53 12 544 34 55 7 11 7 Efficacious 56 20 16 57 1 14 15 58 3 61 2 64 13 7 65 2 127 66 16 4 16 67 2 2 9 68 20 6 16 69 11 4 5 13 70 9 3 3 12 71 24 169 72162 39 920 73 9 191 74 27 424 75 16 11 277 76 11 146 77 17 392 78 14 32379 9 146 80 17 212 81 19 273 82 11 238 84 87 20 223 85 16 10 74 86 64 7206 87 9 16 59

1.-10. (canceled)
 11. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Y is O; the Aring is selected from the group consisting of phenyl and fluorophenyl; Zis selected from the group consisting of

the B ring is selected from the group consisting of

and R is selected from the group consisting of


12. The compound of claim 1, wherein the compound is selected from thegroup consisting of:7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;ethyl(4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;methylrel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;dimethyl2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;tert-butyl{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;ethyl4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1-carboxylate;ethyl4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate;methyl({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate;dimethyl2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;dimethyl2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate;methyl1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate;ethyl(4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin-1-yl)acetate;ethyl[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate;methyl({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate;N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;tert-butyl{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;methyl(2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide;methyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;tert-butyl{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;tert-butyl(4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate;(2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoicacid; 5-tert-butyl 1-methyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylicacid; tert-butyl1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide;dimethyl(2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;ethyl4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;ethyl4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;Methyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylicacid;N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;N-hydroxy-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;3-hydroxypropyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;2-hydroxyethyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;2-methoxyethyl7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;Methyl[(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate;Methyl7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate;7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylicacid;N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide;N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide;and Methyl{[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate;or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutic effective amount of at least onecompound of claim 11, or a pharmaceutically acceptable salt thereof andat least one pharmaceutically acceptable carrier.
 14. The composition ofclaim 13, wherein the composition is in the form of tablets, capsules,intravenous injections, intramuscular injections, local injections,topical creams, gels and ointments, eye drops, eye ointments, eyesprays, ophthalmic suspensions, ophthalmic emulsions, intravitrealinjections, subtenon injections, ophthalmic bioerodible implant, andnon-bioerodible ophthalmic inserts and depots.
 15. A pharmaceuticalcomposition comprising a therapeutic effective amount of at least onecompound of claim 12, or a pharmaceutically acceptable salt thereof andat least one pharmaceutically acceptable carrier.
 16. The composition ofclaim 15, wherein the composition is in the form of tablets, capsules,intravenous injections, intramuscular injections, local injections,topical creams, gels and ointments, eye drops, eye ointments, eyesprays, ophthalmic suspensions, ophthalmic emulsions, intravitrealinjections, subtenon injections, ophthalmic bioerodible implant, andnon-bioerodible ophthalmic inserts and depots.